The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Sang Geon Kim - One of the best experts on this subject based on the ideXlab platform.
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Essential Role of Phosphatidylinositol 3-Kinase-Dependent CCAAT/Enhancer Binding Protein � Activation in the Induction of Glutathione
2013Co-Authors: S-transferase Oltipraz, Keon Wook Kang, Il Je Cho, Chang Ho Lee, Sang Geon KimAbstract:induce genes whose protein products can protect cells from chemical-induced carcinogenesis. Oltipraz, a dithiolthione, exerts chemopreventive responses through glutathione S-transferase (GST) induction. We investigated the role of the CCAAT/enhancer binding protein (C/EBP) in the induction of the GSTA2 gene (alpha class) by Oltipraz and identified the enhancer element(s) responsible for GSTA2 gene expression. Methods: H4IIE rat hepatocyte-derived cells were treated with Oltipraz, and GSTA2 expression was determined by northern and immunoblot analyses. The activation of C/EBP � and � forms and NF-E2-related factor 2 (Nrf2) was assessed by immunochemical assays. C/EBP�-DNA binding activity was determined by subcellular fractionation and electrophoretic mobility shift assays. The role of the C/EBP binding site in the induction of the GSTA
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Oltipraz therapy in patients with liver fibrosis or cirrhosis: A randomized, double-blind, placebo-controlled phase II trial
The Journal of pharmacy and pharmacology, 2011Co-Authors: Sang Geon Kim, Young Mi Kim, Jong Young Choi, Joon Yeol Han, Jeong Won Jang, Hyun Cho, Chae Yoon Chon, Dong Hoo Lee, Ja June JangAbstract:Objectives Oltipraz, a cancer chemopreventive agent, has an anticirrhotic effect in animals. A phase II trial was designed to investigate the preliminary efficacy of Oltipraz therapy in liver fibrosis or cirrhosis. Methods Of 83 patients who were randomized to receive placebo, Oltipraz 60 mg bid or Oltipraz 90 mg qd for 24 weeks, 68 completed the study without any major protocol violation. Pre- and post-treatment liver biopsies, and blood fibrosis markers were assessed. Key findings Twenty-four weeks of Oltipraz treatment showed no significant differences in the proportions of patients showing an improvement in histological outcomes, including Ishak fibrosis score. In the Oltipraz 60 mg bid group, there was a trend of decreases in hepatic collagen area and plasma transforming growth factor-β1 (TGF-β1, a blood fibrosis marker) levels from baseline to week 24. In the per-protocol population (n = 68), decreases in plasma TGF-β1 correlated with those in the Ishak fibrosis score, suggesting that circulating TGF-β1 serves a possible indicator for fibrosis treatment. Conclusions No significant differences in liver histological outcomes were seen among the three treatment groups in this 24-week pilot study. Our finding indicates an association between TGF-β1 repression and improvement in the histological index of fibrosis.
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pharmacokinetic interaction between Oltipraz and dimethyl 4 4 dimethoxy 5 6 5 6 dimethylene dioxybiphenyl 2 2 dicarboxylate ddb after single intravenous and oral administration to rats
Journal of Pharmacy and Pharmacology, 2010Co-Authors: Soo K. Bae, Eun Jung Kim, Suk Jae Chung, Sang Geon Kim, Myung Gull LeeAbstract:The aim of this study was to report the pharmacokinetic interaction between Oltipraz (50 mg kg(-1)) and dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate (DDB, 10 mg kg(-1)) after single intravenous and oral administration to rats. After intravenous administration of Oltipraz plus DDB, the area under the plasma concentration-time curve from time zero to time infinity (AUC) of Oltipraz was significantly greater (1440 vs 1740 microg min mL(-1)) than that after Oltipraz alone. This was not due to slower clearances of Oltipraz after Oltipraz plus DDB since the total body, renal and nonrenal clearances were comparable between the two groups of rats. It could be due to a decrease in tissue binding of Oltipraz by DDB. The apparent volume of distribution at steady state (Vd(ss)) of DDB was significantly smaller (7060 vs 4650 mL kg(-1)) than after Oltipraz alone. After oral administration of Oltipraz plus DDB, the AUC of olitpraz was also significantly greater (479 vs 583 microg min mL(-1)) than that after Oltipraz alone. This was not due to increased absorption of Oltipraz from the rat gastrointestinal tract after Oltipraz plus DDB but again could be due to a decrease in Vd(ss) of Oltipraz by DDB. However, after both intravenous and oral administration, the pharmacokinetic parameters of DDB were comparable between DDB alone and DDB plus Oltipraz, indicating that Oltipraz did not greatly affect the pharmacokinetics of DDB in rats.
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Antioxidant and mitochondrial protective effects of oxidized metabolites of Oltipraz
Expert opinion on drug metabolism & toxicology, 2010Co-Authors: Songhwa Choi, Young Mi Kim, Jungmin Lee, Sang Geon KimAbstract:Importance of the field: Comprehensive studies indicate that Oltipraz exerts cancer chemopreventive effects. Oltipraz has other therapeutic potentials, which include anti-fibrotic effect, inhibition of insulin resistance, mitochondrial protection and cytoprotective effect against oxidative stress. Although antioxidant mechanisms may account for its cancer chemopreventive effect, details on the molecular mechanism still remain to be clarified.Areas covered in this review: Two major metabolic pathways of Oltipraz include oxidative desulfuration of the thione to yield 4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiol-3-one and molecular rearrangement to 7-methyl-6,8-bis(methylthio)H-pyrrolo[1,2-a]pyrazine. In addition to the diverse pharmacological effects of Oltipraz, the oxidized metabolites may have distinct biological effects on cell survival. The AMP-activated protein kinase pathway has been recognized as a key cascade for mitochondrial protection and cell survival events, which can be activated by the oxidized ...
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Oltipraz and dithiolethione congeners inhibit hypoxia inducible factor 1α activity through p70 ribosomal s6 kinase 1 inhibition and h2o2 scavenging effect
Molecular Cancer Therapeutics, 2009Co-Authors: Woo Hyung Lee, Young Woo Kim, Jae Hoon Choi, Samuel Carroll Brooks, Miock Lee, Sang Geon KimAbstract:Hypoxia-inducible factor-1α (HIF-1α) induces tumor proliferation, angiogenesis and metastasis. Reactive oxygen species, hypoxia, and growth factor stimulation induce HIF-1α, and the augmented HIF-1α activity confers upon cancer cells the ability to adapt to microenvironments. Oltipraz is a cancer chemopreventive agent and has an inhibitory effect on angiogenesis and tumor growth. Nonetheless, the molecular mechanism of tumor inhibition is as yet unclear. This study investigated whether Oltipraz and its congeners inhibit HIF-1α activity and, if so, the molecular basis of inhibition. Oltipraz and other 1,2-dithiole-3-thiones have the ability to prevent insulin- or hypoxia-induced HIF-1α expression through an increase in ubiquitination, thereby accelerating HIF-1α degradation and inhibiting HIF-1α–dependent gene transcription. Transfection of cells with a constitutively active mutant of p70 ribosomal S6 kinase-1 (CA-S6K1) increased the basal and insulin-inducible HIF-1α activity. CA-S6K1 overexpression reversed HIF-1α inhibition by rapamycin (a mammalian target of rapamycin/S6K1 inhibitor). However, the inhibitory effect of Oltipraz on HIF-1α was not reversed by CA-S6K1 despite its S6K1 inhibition. The failure of dominant negative mutant AMP-activated protein kinase-α to restore the ability of insulin to increase HIF-1α against Oltipraz excluded the possible role of AMP-activated protein kinase activation in the action of Oltipraz. Oltipraz treatment abrogated insulin-induced H2O2 production, thereby preventing H2O2-enhanced HIF-1α expression and promoting its ubiquitination and degradation. In an animal model, tumor regression by Oltipraz was accompanied by decreases in microvessel density and vascular endothelial growth factor induction. Oltipraz inhibits HIF-1α activity and HIF-1α–dependent tumor growth, which may result from a decrease in HIF-1α stability through S6K1 inhibition in combination with an H2O2-scavenging effect. [Mol Cancer Ther 2009;8(10):2791–802]
Thomas W. Kensler - One of the best experts on this subject based on the ideXlab platform.
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Chemoprevention by Inducers of Carcinogen Detoxication Enzymes
2013Co-Authors: Thomas W. KenslerAbstract:One of the major mechanisms of chemical protection against carcinogenesis, mutagenesis, and other forms of toxicity mediated by electrophiles is the induction of enzymes involved in their metabolism, particularly phase 2 enzymes such as glutathione S-transferases (GSTs), uridine diphosphate-glucuronosyltransferases, and NAD(P)H:quinone reductase. Furthermore, induction of phase 2 enzymes appears to be a sufficient condition for obtaining chemoprevention and can be achieved in many target tissues by administering any of a diverse array of naturally occurring and synthetic chemical agents. One class of chemopreventive agents, 1,2-dithiole-3-thiones, was developed on the basis of their potent activity in rodent tissues as inducers of GSTs. A substituted dithiolethione, Oltipraz 14-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thionel, is an effective inhibitor of aflatoxin Bl-mediated hepatocarcinogenesis in the rat. Oltipraz produces dramatic decreases in the levels of aflatoxin-DNA adducts in the liver as well as in the urinary levels of the depurination product aflatoxin-N7-guanine. Corresponding increases are seen in the biliary elimination of aflatoxin-glutathione conjugates. Administration of Oltipraz results in 3- to 4-fold increases in hepatic cytosolic GST activities and mRNA levels for some x, p and X isoforms. Nuclear run-on assays have indicated that Oltipraz treatment elevates rates of transcription o
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Oltipraz chemoprevention trial in Qidong, People's Republic of China: unaltered oxidative biomarkers.
Free radical biology & medicine, 2006Co-Authors: Bente Glintborg, Thomas W. Kensler, Allan Weimann, H E PoulsenAbstract:Aflatoxin, which leads to formation of carcinogen-DNA adducts as well as oxidized DNA, is a well-known risk factor for development of hepatocellular carcinoma. The aim of the present study was to investigate if the chemopreventive agent Oltipraz had an effect on DNA oxidation measured as oxidized guanine derivatives in urine among healthy individuals living in a region of China at high risk of exposure to aflatoxin and development of hepatocellular carcinoma. Two hundred thirty-three healthy residents of Qidong, PRC, were randomized to 8 weeks treatment with placebo, Oltipraz 125 mg daily, or Oltipraz 500 mg weekly, with a subsequent 8-week follow-up period. Urine samples were collected as overnight voids. Samples collected 4 weeks into the treatment period and 6 weeks into the follow-up period were analyzed for oxidized guanine derivatives with a HPLC-MS/MS method. A repeated-measures analysis of variance showed no significant differences between the randomization groups regarding changes in oxidized guanine derivatives. In the present double-blind, randomized, placebo-controlled trial performed among healthy individuals, Oltipraz had no major effect on oxidative DNA damage. Mechanisms other than prevention of oxidative DNA damage may be of higher importance when Oltipraz is used as a chemopreventive agent in humans.
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Phase 2 Enzyme Induction by the Major Metabolite of Oltipraz
Chemical research in toxicology, 2003Co-Authors: Jacobus P. Petzer, Thomas W. Kensler, Mettachit Navamal, Jesse K. Johnson, Mi Kyoung Kwak, James C. FishbeinAbstract:Treatment for 48 h of murine Hepa 1c1c7 cells in culture with the cancer chemopreventive Oltipraz (1) followed by addition of CD(3)I and immediate cell lysis yields, by LC/MS analysis, three isotopomers of the methylated pyrrolopyrazine (2), a known human metabolite of Oltipraz. The major isotopomer (58%) is the one containing two CD(3)- groups attached to the pendant sulfur atoms of the pyrrolopyrazine ring, the others containing one CD(3)- and one CH(3)- group or two CH(3)- groups. It is concluded from this that the unmethylated pyrrolopyrazine (4) is the major metabolite of Oltipraz. Prodrugs 5 and 6, which have been shown to rapidly generate 4 in the presence of GSH at physiological pH, induce the phase 2 enzyme NQO1 in Hepa 1c1c7 cells with potencies on par with Oltipraz itself: CD(NQO1) = 14.4 +/- 1.3, 20.1 +/- 4.6, and 23.6 +/- 1.6 microM for Oltipraz, 5, and 6, respectively. Pretreatment of Oltipraz, 5, and 6 in cell culture media with 1 mM GSH, which is shown to immediately convert 5 and 6 to 4, followed by incubation with Hepa 1c1c7 cells shows similar potencies for Oltipraz and the (decomposed) produrgs, with CD(NQO1) = 18.0 +/- 4.4 microM for 5, 17.8 +/- 0.2 microM for 6, and 13.5 +/- 1.4 microM for Oltipraz. Treatment with compound 6 of murine hepatoma cells containing a luciferase gene under the control of the antioxidant response element (ARE) from the mouse heme oxygenase (ho-1) gene elicits induction of luciferase activity, CD = 35.8 +/- 2.8 microM, somewhat greater than the potency than Oltipraz itself. Western blots of nuclear proteins isolated from Hepa 1c1c7 cells and probed with anti-Nrf2 indicate that as compared to vehicle DMSO, compound 6 stimulates nuclear translocation of Nrf2 from the cytosol. From this study, it is concluded that the major metabolite of the cancer chemopreventive Oltipraz is a phase 2 enzyme inducer of comparable potency that activates the ARE and initiates nuclear translocation of transcription factor Nrf 2.
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interactive effects of nrf2 genotype and Oltipraz on benzo a pyrene dna adducts and tumor yield in mice
Carcinogenesis, 2003Co-Authors: Minerva Ramosgomez, Masayuki Yamamoto, Ken Itoh, Patrick Dolan, Thomas W. KenslerAbstract:The cancer chemopreventive actions of Oltipraz (4-methyl-5-[2-pyrazinyl]-1,2-dithiole-3-thione) have been primarily associated with the induction of phase 2 detoxifying enzymes through transcriptional activation of the antioxidant response element (ARE) in the promoter regions of these genes. The transcription factor Nrf2 has been shown to bind to and activate AREs. Previously, we demonstrated that nrf2-deficient mice had low basal expression of phase 2 enzymes and were substantially more susceptible to benzo[a]pyrene (B[a]P)-induced neoplasia of the forestomach than wild-type. Moreover, loss of Nrf2 abrogated the chemopreventive action of Oltipraz, when administered 48 h before B[a]P, an interval allowing maximal induction of many phase 2 enzymes. Oltipraz also inhibits some cytochrome P450s involved in the bioactivation of B[a]P. In the present study we observed that Oltipraz had no protective effect on tumor burden in the forestomach of nrf2-deficient mice when administered 1 h before B[a]P, a timeline that selectively optimizes for possible inhibitory effects on cytochrome P450s. To evaluate the role of nrf2 genotype on B[a]P disposition, levels of B[a]P-DNA adducts were measured as tetrols released from DNA isolated from target (forestomach) and non-target tissues (liver) of wild-type and nrf2-deficient mice treated with either vehicle or Oltipraz 1 or 48 h before B[a]P. Levels of B[a]P-DNA adducts in forestomach were significantly higher in nrf2-deficient compared with wild-type mice. Oltipraz treatment at 1 or 48 h before B[a]P had no protective effect on forestomach tetrol levels in nrf2-deficient mice, whereas a significant reduction was observed in wild-type mice treated with Oltipraz 48 h, but not 1 h, before carcinogen. Combining all treatments and genotypes, there was a strong correlation (R(2) = 0.91) between levels of B[a]P-DNA adducts in forestomach and subsequent yield of tumors. In contrast to the results in forestomach, nrf2 genotype did not modify hepatic B[a]P-DNA adduct levels while both Oltipraz treatments were protective, suggesting that Nrf2-independent mechanisms (e.g. P450 inhibition) for Oltipraz can also occur in vivo in some tissues.
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reduction of aflatoxin b1 adduct biomarkers by Oltipraz in the tree shrew tupaia belangeri chinensis
Cancer Letters, 2000Co-Authors: Liu Liang Qin, Thomas W. Kensler, John D. Groopman, Patricia A. Egner, Jiasheng Wang, B D RoebuckAbstract:Abstract The risk of liver cancer is greatest in people both infected with hepatitis B virus (HBV) and highly exposed to aflatoxin B 1 (AFB 1 ). The tree shrew ( Tupaia belangeri chinensis ) is a unique species that can be infected with human HBV, is susceptible to AFB 1 -induced liver cancer, and shows a synergistic interaction between HBV and AFB 1 for liver cancer. In this regard, the tree shrew may be useful for evaluating experimental chemoprevention strategies relevant to high-risk human populations as it mirrors the human epidemiology of liver cancer. To begin developing the model for chemoprevention study, two groups of tree shrews were fed 400 μg AFB 1 /kg b.wt. in milk daily for 4 weeks. One week prior to AFB 1 administration, one group also received Oltipraz (0.5 mmol/kg, p.o.) daily for 5 weeks. At weekly intervals, 1 ml of blood and a 24-h urine sample were obtained from each animal. Aflatoxin-albumin adducts in serum were determined by a radioimmunological assay and aflatoxin-N 7 -guanine adducts in urine were measured by HPLC. Aflatoxin-albumin adducts increased rapidly in 2 weeks to plateau at 20 pmol/mg protein, and they diminished after cessation of AFB 1 exposure. Oltipraz significantly attenuated the overall burden of aflatoxin–albumin adducts throughout the exposure period with a median reduction of 80%. In a single cross-sectional analysis at the end of AFB 1 dosing, Oltipraz treatment decreased urinary aflatoxin-N 7 -guanine by 93%. Collectively, these results indicate that Oltipraz reduces AFB 1 risk biomarkers in the tree shrew in a manner similar to that observed in rodents and humans, and establishes a rationale to evaluate cancer chemoprevention by Oltipraz in human HBV-infected, AFB 1 exposed tree shrews.
Bill D. Roebuck - One of the best experts on this subject based on the ideXlab platform.
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Identification of dithiolethiones with better chemopreventive properties than Oltipraz.
Carcinogenesis, 1998Co-Authors: Yulia Y. Maxuitenko, Denise L. Macmillan, Thomas W. Kensler, Adam H Libby, Thomas J Curphey, H. Howard Joyner, Bill D. RoebuckAbstract:Oltipraz and related dithiolethiones are an important class of chemopreventive agents. Studies were undertaken to identify cancer chemopreventive dithiolethiones more active than Oltipraz. Largely based upon enzyme induction activities in vitro, 17 dithiolethiones, including Oltipraz, were analyzed for their ability to induce hepatic phase II enzyme activities in vivo. Of these compounds, 15 produced greater induction of NAD(P)H:quinone reductase and 11 yielded greater induction of glutathione S-transferase than Oltipraz. All 17 dithiolethiones were then tested for their ability to inhibit acute hepatotoxicity by aflatoxin B 1 (AFB 1 ), which previously has been shown to be an intermediate predictor of chemopreventive activity. Rats were pretreated with dithiolethiones (0.3 mmol/kg body wt, three times a week per os) and challenged with two acutely toxic doses of AFBI (0.5 mg/kg body wt, once daily for two successive days per os). Inhibition of hepatotoxicity was measured by changes in body weight gain during AFB 1 challenge, reduction in levels of hepatic enzymes in serum and diminution of bile duct cell proliferation. Nine dithiolethiones spanning a range of responses in this toxicity screen were further tested for their ability to prevent AFBI-induced tumorigenicity, as assessed by a reduction in hepatic burden of putative preneoplastic foci. Six dithiolethiones were found to be considerably more effective than Oltipraz in preventing AFB 1 -induced tumorigenesis. In general, dithiolethiones that were very effective in inhibition of acute hepatotoxicity were also found to be effective in prevention of hepatic tumorigenesis.
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predictive value of molecular dosimetry individual versus group effects of Oltipraz on aflatoxin albumin adducts and risk of liver cancer
Cancer Epidemiology Biomarkers & Prevention, 1997Co-Authors: Thomas W. Kensler, John D. Groopman, Patricia A. Egner, Adrianne E Rogers, Patrick Dolan, Alvaro Muñoz, Stephen J Gange, Bill D. RoebuckAbstract:Studies in animals and humans have established serum aflatoxin-albumin adducts as biomarkers of exposure to aflatoxin B1 (AFB1), a food-borne hepatocarcinogen. To assess the utility of measurements of aflatoxin-albumin adducts to predict risk of hepatocellular carcinoma (HCC), 123 male F344 rats were dosed with 20 microg of AFB1 daily for 5 weeks after randomization into three groups: no intervention; delayed-transient (500 ppm of Oltipraz, weeks 2 and 3 relative to AFB1); or persistent (500 ppm Oltipraz, weeks -1 to 5). Serial blood samples were collected from each animal at weekly intervals throughout aflatoxin B1 exposure and assayed for levels of aflatoxin-albumin by radioimmune assay. Area under the curve (AUC) values for aflatoxin-albumin adducts decreased 20 and 39% in the delayed-transient and persistent Oltipraz intervention groups, respectively, as compared to no intervention. Similarly, the total incidence of HCC dropped from 83 to 60% (P = 0.03) and 48% (P < 0.01) in these groups. Tumor multiplicity was also reduced in the two Oltipraz intervention groups, whereas time to HCC was increased. Mononuclear cell leukemia, a common neoplasm in F344 rats, was seen in 39% of the control animals, whereas the two Oltipraz interventions reduced incidence to 18% (P = 0.05) and 13% (P = 0.01), respectively. Overall, a significant association was seen between biomarker AUC and risk of HCC (P = 0.01). However, when the predictive value of aflatoxin-albumin adducts was assessed within treatment groups, there was no association between AUC and risk of HCC (P = 0.56). Thus, aflatoxin-albumin adducts can be useful for monitoring population-based changes induced by interventions, such as in chemoprevention trials, but have limited utility in identifying individuals destined to develop HCC. As a consequence, the use of this biomarker in quantitative risk assessment should be pursued cautiously.
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Intermittent Dosing with Oltipraz: Relationship between Chemoprevention of Aflatoxin-induced Tumorigenesis and Induction of Glutathione S-Transferases
Cancer research, 1995Co-Authors: Thomas Primiano, Bill D. Roebuck, Patricia A. Egner, Thomas R. Sutter, Gary J. Kelloff, Thomas W. KenslerAbstract:Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione] protects against chemical carcinogenesis in several animal models and is currently under evaluation as a possible chemopreventive agent in humans. Ideally, clinical chemopreventive interventions use dosing regimens that maximize efficacy while minimizing toxicity. Toward this end, the chemopreventive efficacy achieved by administration of intermittent doses of oltipaz was evaluated in rats. F344 rats were treated with Oltipraz (0.5 mmol/kg, p.o.) once weekly, twice weekly, or daily over a 5-week period. After the first week, all rats were gavaged with 20 µg/kg of aflatoxin B1 for 28 consecutive days. Livers were analyzed 2 months after the last aflatoxin B1 dose, and the volume of liver occupied by glutathione S -transferase (GST)-P positive foci, a presumptive marker of neoplasia, was observed to be decreased >95%, >97%, or >99% in livers of rats receiving once-, twice-weekly or daily Oltipraz treatments, respectively. The chemopreventive actions of Oltipraz have been associated with increases in the levels of phase 2 detoxifying enzymes, such as the glutathione S -transferase isozymes. Accordingly, GST conjugation activity measured with 1-chloro-2,4-dinitrobenzene as substrate increased 1.5-, 1.8-, or 2.4-fold for the once-weekly, twice-weekly or daily treatments, respectively, throughout a 7-day period. Quantitative HPLC analyses of GST subunits 24 h after 2 or 7 daily administrations of Oltipraz showed that the levels of subunits Yb1, Yp, Yc2, and Ya2 were increased with maximum elevations of 5.6-, 11.1-, 6.4-, and 10.4-fold, respectively. In comparison, levels of subunits Yb2 and Yc1 were modestly elevated 1.8- to 2.6-fold, respectively, whereas subunit Ya1 was not induced. Remarkably, the levels of subunit Yp and Ya2 remained elevated ∼2.3-fold 7 days after a single dose of Oltipraz. In contrast, the levels of subunits Yb1 and Yc2 diminished to approximate control levels within 7 days after a single dose of Oltipraz. GST mRNA levels for Ya, Yb, and Yp were measured by Northern blot analysis and were found to be elevated maximally to 13.7-, 13.5-, and 3.9-fold, respectively, after two daily Oltipraz doses. Interestingly, GST Ya and Yb mRNA diminished to constitutive levels after 7 daily doses of Oltipraz, with no corresponding decreases in GST subunit or activity levels. The levels of GST Ya and Yb mRNA decreased to constitutive levels within 4 days after a single Oltipraz administration, whereas GST Yp mRNA levels remained elevated throughout the 7-day follow-up period. These results suggest that the protracted pharmacodynamic actions of Oltipraz on enzyme induction may account for the marked reduction in the hepatic burden of aflatoxin B1-induced putative preneoplastic tumors after intermittent dosing. Consequently, scheduling of intermittent dosing protocols may sustain efficacy while improving drug tolerance and patient compliance over long-term treatments. These properties of Oltipraz increase its attractiveness for clinical chemopreventive interventions.
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Transient Intervention with Oltipraz Protects against Aflatoxin-induced Hepatic Tumorigenesis
Cancer research, 1993Co-Authors: Mary G. Bolton, Yulia Y. Maxuitenko, Bill D. Roebuck, John D. Groopman, Alvaro Muñoz, Lisa P. Jacobson, Thomas W. KenslerAbstract:Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione] protects against aflatoxin B1-induced hepatocarcinogenesis in rats when fed before and during carcinogen exposure; however, such an exposure-chemoprotection intervention paradigm is not directly relevant to most human populations. To model and assess the possible efficacy of short term interventions targeted at individuals at risk for sustained exposure to aflatoxins, 175-g male F344 rats were treated daily with 25 micrograms of aflatoxin B1, p.o., for 28 days. One week after the start of aflatoxin B1 exposure, half of the animals were fed a diet supplemented with 0.075% Oltipraz for 10 days; these rats were then restored to the unsupplemented AIN-76A diet for the remainder of the experimental period. Livers were analyzed 2 or 3 months after the last aflatoxin B1 dose for burden of glutathione S-transferase P (GST-P)-positive foci, as an index of presumptive preneoplastic tumors. The transient intervention with Oltipraz reduced the volume percent of hepatic GST-P-positive foci by 54% (P = 0.047) and 72% (P = 0.004) at 2 and 3 months, respectively. A strong positive correlation was also observed between the extent of fibrosis in the livers of these animals and the hepatic burden of GST-P-positive foci, implying that cytotoxicity is associated with the tumorigenic process. This protection may reflect alterations in the metabolism and disposition of aflatoxin B1 induced by Oltipraz. Glutathione S-transferase catalyze the detoxication of aflatoxin-8,9-oxide and were found to be rapidly induced in the livers of animals after the beginning of the Oltipraz intervention. Glutathione S-transferase activity remained significantly (P < 0.05) higher until 9 days after the end of the Oltipraz intervention. In contrast, levels of hepatic aflatoxin-DNA adducts were not significantly reduced until 4 days after the beginning of the intervention but remained significantly (P < 0.05) lower up to 11 days after the end of the intervention. The cumulative reduction in levels of hepatic aflatoxin-DNA adducts (approximately 25%) by the Oltipraz intervention underestimated the reduction in the hepatic burden of GST-P-positive foci. The significant protection against presumptive preneoplastic tumors, despite the delay of intervention, suggests that Oltipraz may exert substantial activity against the cytotoxic and autopromoting action of repeated exposures to aflatoxin B1 and supports the utility of intervention trials with Oltipraz in individuals chronically consuming aflatoxin B1-contaminated foods, particularly in regions with high incidences of liver cancer.
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SHORT COMMUNICATION: Evaluation of the post-initiation effects of Oltipraz on aflatoxin B1-induced preneoplastic foci in a rat model of hepatic tumorigenesis
Carcinogenesis, 1993Co-Authors: Yulia Y. Maxuitenko, Denise L. Macmillan, Thomas W. Kensler, Bill D. RoebuckAbstract:Previous studies have demonstrated that ingestion of 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione (Oltipraz) during the aflatoxin B1 (AFB1) treatment phase completely prevented hepatic cancer. In this study we evaluated the effect of feeding Oltipraz during the post-AFB1 treatment phase. Fifty-five male F344 rats were divided into five groups. All rats were gavaged with 25 micrograms AFB1/rat, five times a week for two successive weeks. The rats were fed the Oltipraz-supplemented diet according to three different feeding regimes: during the AFB1 treatment phase (1 week prior to, during and 1 week after the last gavage with AFB1); during the post-treatment phase; or throughout the entire time of the experiment. Phenobarbital-supplemented diet was fed during post-treatment phase to one group and this was used as a positive control for the promotion of AFB1-induced focal growth. The burden of putative, preneoplastic, hepatic glutathione S-transferase P-positive foci was evaluated at 13 weeks after the AFB1 treatment phase. As seen previously, Oltipraz fed during the AFB1 treatment phase significantly inhibited focal development, i.e. the volume percent of the liver occupied with foci was reduced by 87%. Oltipraz when fed during the post-treatment phase neither inhibited nor enhanced focal development.
John D. Groopman - One of the best experts on this subject based on the ideXlab platform.
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reduction of aflatoxin b1 adduct biomarkers by Oltipraz in the tree shrew tupaia belangeri chinensis
Cancer Letters, 2000Co-Authors: Liu Liang Qin, Thomas W. Kensler, John D. Groopman, Patricia A. Egner, Jiasheng Wang, B D RoebuckAbstract:Abstract The risk of liver cancer is greatest in people both infected with hepatitis B virus (HBV) and highly exposed to aflatoxin B 1 (AFB 1 ). The tree shrew ( Tupaia belangeri chinensis ) is a unique species that can be infected with human HBV, is susceptible to AFB 1 -induced liver cancer, and shows a synergistic interaction between HBV and AFB 1 for liver cancer. In this regard, the tree shrew may be useful for evaluating experimental chemoprevention strategies relevant to high-risk human populations as it mirrors the human epidemiology of liver cancer. To begin developing the model for chemoprevention study, two groups of tree shrews were fed 400 μg AFB 1 /kg b.wt. in milk daily for 4 weeks. One week prior to AFB 1 administration, one group also received Oltipraz (0.5 mmol/kg, p.o.) daily for 5 weeks. At weekly intervals, 1 ml of blood and a 24-h urine sample were obtained from each animal. Aflatoxin-albumin adducts in serum were determined by a radioimmunological assay and aflatoxin-N 7 -guanine adducts in urine were measured by HPLC. Aflatoxin-albumin adducts increased rapidly in 2 weeks to plateau at 20 pmol/mg protein, and they diminished after cessation of AFB 1 exposure. Oltipraz significantly attenuated the overall burden of aflatoxin–albumin adducts throughout the exposure period with a median reduction of 80%. In a single cross-sectional analysis at the end of AFB 1 dosing, Oltipraz treatment decreased urinary aflatoxin-N 7 -guanine by 93%. Collectively, these results indicate that Oltipraz reduces AFB 1 risk biomarkers in the tree shrew in a manner similar to that observed in rodents and humans, and establishes a rationale to evaluate cancer chemoprevention by Oltipraz in human HBV-infected, AFB 1 exposed tree shrews.
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predictive value of molecular dosimetry individual versus group effects of Oltipraz on aflatoxin albumin adducts and risk of liver cancer
Cancer Epidemiology Biomarkers & Prevention, 1997Co-Authors: Thomas W. Kensler, John D. Groopman, Patricia A. Egner, Adrianne E Rogers, Patrick Dolan, Alvaro Muñoz, Stephen J Gange, Bill D. RoebuckAbstract:Studies in animals and humans have established serum aflatoxin-albumin adducts as biomarkers of exposure to aflatoxin B1 (AFB1), a food-borne hepatocarcinogen. To assess the utility of measurements of aflatoxin-albumin adducts to predict risk of hepatocellular carcinoma (HCC), 123 male F344 rats were dosed with 20 microg of AFB1 daily for 5 weeks after randomization into three groups: no intervention; delayed-transient (500 ppm of Oltipraz, weeks 2 and 3 relative to AFB1); or persistent (500 ppm Oltipraz, weeks -1 to 5). Serial blood samples were collected from each animal at weekly intervals throughout aflatoxin B1 exposure and assayed for levels of aflatoxin-albumin by radioimmune assay. Area under the curve (AUC) values for aflatoxin-albumin adducts decreased 20 and 39% in the delayed-transient and persistent Oltipraz intervention groups, respectively, as compared to no intervention. Similarly, the total incidence of HCC dropped from 83 to 60% (P = 0.03) and 48% (P < 0.01) in these groups. Tumor multiplicity was also reduced in the two Oltipraz intervention groups, whereas time to HCC was increased. Mononuclear cell leukemia, a common neoplasm in F344 rats, was seen in 39% of the control animals, whereas the two Oltipraz interventions reduced incidence to 18% (P = 0.05) and 13% (P = 0.01), respectively. Overall, a significant association was seen between biomarker AUC and risk of HCC (P = 0.01). However, when the predictive value of aflatoxin-albumin adducts was assessed within treatment groups, there was no association between AUC and risk of HCC (P = 0.56). Thus, aflatoxin-albumin adducts can be useful for monitoring population-based changes induced by interventions, such as in chemoprevention trials, but have limited utility in identifying individuals destined to develop HCC. As a consequence, the use of this biomarker in quantitative risk assessment should be pursued cautiously.
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SHORT COMMUNICATION: Inhibition of aflatoxin M1 excretion in rat urine during dietary intervention with Oltipraz
Carcinogenesis, 1996Co-Authors: Peter F. Scholl, Thomas W. Kensler, Steven M. Musser, John D. GroopmanAbstract:4-Methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione (Oltipraz) is an effective chemopreventive agent against several classes of carcinogens in many target organs. Induction of carcinogen detoxication enzymes, particularly glutathione S-transferases, appears to be an important component of the protective actions of Oltipraz. It has recently been observed that addition of Oltipraz to rat liver microsomes or to cultured human hepatocytes blocks the oxidative metabolism of aflatoxin B1 (AFB1) to its 8,9-oxide and the hydroxylated derivative aflatoxin Ml (AFM1). 0ltipraz is a competitive and perhaps irreversible inhibitor of cytochromes P450 1A2 and 3A4. To determine whether Oltipraz can affect cytochrome P450-dependent metabolism of AFB1 in vivo we have assessed the effect of Oltipraz on the urinary excretion of oxidative metabolites of AFB1 before, during and after a transient intervention. Male F344 rats, housed individually in glass metabolism cages, were gavaged daily with 25 microg [3H]AFB1 for 28 consecutive days. Starting on day 6 and extending to day 16 half of the rats were fed a diet supplemented with 0.075% Oltipraz. Sequential 24 h urine samples were collected and a subset analyzed for AFB1 metabolites. AFM1 was the major metabolite detected in all urine samples, accounting for 2-6% of the administered dose. The excretion of AFM1 was greatly reduced (77%) during the active phase of the intervention, when Oltipraz was added to the diet, but rapidly returned to control levels after cessation of Oltipraz administration. This inhibition of AFM1 excretion was not seen in animals receiving Oltipraz by gavage 24 h prior to dosing with AFB1. Collectively these data are consistent with the view that Oltipraz or a short-lived metabolite inhibits cytochrome P450 1A2 in vivo.
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Transient Intervention with Oltipraz Protects against Aflatoxin-induced Hepatic Tumorigenesis
Cancer research, 1993Co-Authors: Mary G. Bolton, Yulia Y. Maxuitenko, Bill D. Roebuck, John D. Groopman, Alvaro Muñoz, Lisa P. Jacobson, Thomas W. KenslerAbstract:Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione] protects against aflatoxin B1-induced hepatocarcinogenesis in rats when fed before and during carcinogen exposure; however, such an exposure-chemoprotection intervention paradigm is not directly relevant to most human populations. To model and assess the possible efficacy of short term interventions targeted at individuals at risk for sustained exposure to aflatoxins, 175-g male F344 rats were treated daily with 25 micrograms of aflatoxin B1, p.o., for 28 days. One week after the start of aflatoxin B1 exposure, half of the animals were fed a diet supplemented with 0.075% Oltipraz for 10 days; these rats were then restored to the unsupplemented AIN-76A diet for the remainder of the experimental period. Livers were analyzed 2 or 3 months after the last aflatoxin B1 dose for burden of glutathione S-transferase P (GST-P)-positive foci, as an index of presumptive preneoplastic tumors. The transient intervention with Oltipraz reduced the volume percent of hepatic GST-P-positive foci by 54% (P = 0.047) and 72% (P = 0.004) at 2 and 3 months, respectively. A strong positive correlation was also observed between the extent of fibrosis in the livers of these animals and the hepatic burden of GST-P-positive foci, implying that cytotoxicity is associated with the tumorigenic process. This protection may reflect alterations in the metabolism and disposition of aflatoxin B1 induced by Oltipraz. Glutathione S-transferase catalyze the detoxication of aflatoxin-8,9-oxide and were found to be rapidly induced in the livers of animals after the beginning of the Oltipraz intervention. Glutathione S-transferase activity remained significantly (P < 0.05) higher until 9 days after the end of the Oltipraz intervention. In contrast, levels of hepatic aflatoxin-DNA adducts were not significantly reduced until 4 days after the beginning of the intervention but remained significantly (P < 0.05) lower up to 11 days after the end of the intervention. The cumulative reduction in levels of hepatic aflatoxin-DNA adducts (approximately 25%) by the Oltipraz intervention underestimated the reduction in the hepatic burden of GST-P-positive foci. The significant protection against presumptive preneoplastic tumors, despite the delay of intervention, suggests that Oltipraz may exert substantial activity against the cytotoxic and autopromoting action of repeated exposures to aflatoxin B1 and supports the utility of intervention trials with Oltipraz in individuals chronically consuming aflatoxin B1-contaminated foods, particularly in regions with high incidences of liver cancer.
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protection against aflatoxin b1 induced hepatocarcinogenesis in f344 rats by 5 2 pyrazinyl 4 methyl 1 2 dithiole 3 thione Oltipraz predictive role for short term molecular dosimetry
Cancer Research, 1991Co-Authors: B D Roebuck, John D. Groopman, Adrianne E Rogers, Thomas W. KenslerAbstract:Previous studies have demonstrated that dietary administration of the schistosomicidal drug 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione (Oltipraz) ameliorates the hepatotoxicity of aflatoxin B1 (AFB1). Notably, mortality, altered hepatic function, hepatic AFB1-DNA adduct levels, and expression of hepatic enzyme-altered foci were markedly reduced in the rat by concurrent feeding of Oltipraz during exposures to AFB1. Collectively, these studies prompted us to evaluate the chemoprotective properties of Oltipraz against AFB1-induced liver cancer. In addition, preliminary molecular dosimetry studies were undertaken to determine the utility of measurements of urinary aflatoxin- N 7-guanine excretion as a marker of relative risk for hepatocarcinogenesis in AFB1-exposed rats. For the carcinogenesis studies, 5-wk-old male F344 rats were randomly divided into two groups. One group (55 rats) received the AIN-76A diet, and the other group (56 rats) received the AIN-76A diet supplemented with 0.075% Oltipraz. The Oltipraz-supplemented diet was fed for 4 wk. Beginning 1 wk after starting the experimental diets, all rats in both groups received 25 µg of AFB1/rat/day by gavage for 5 days per wk over the next 2 wk. One wk following cessation of dosing with AFB1, Oltipraz was removed from the diet, and all rats were fed the AIN-76A diet for the remainder of the experiment. At 3 mo after dosing, livers of ten sentinel rats from each group were analyzed for the burden of γ-glutamyltranspeptidase-positive foci. In accord with previous findings, rats fed the Oltipraz-supplemented diet exhibited substantial reductions in the focal burden (97% reduction; P < 0.05) of these AFB1-induced lesions. The remaining rats were maintained for the cancer study until they became moribund or the termination of the experiment at 23 mo. Gross liver lesions were identified at autopsy and confirmed by microscopic evaluation. An 11% incidence of hepatocellular carcinoma was observed in the AFB1-treated, control diet-fed rats. An additional 9% of this group had hepatocellular adenomas. Oltipraz afforded complete protection against both AFB1-induced hepatocellular neoplasms. Using Kaplan-Meier survival analyses, rats in the Oltipraz group had a significantly ( P < 0.02) longer life span and an increased survival free of liver tumors ( P < 0.0002). Molecular dosimetry studies used rats fed either the Oltipraz-supplemented or control diet for 1 wk and then challenged with a single dose of AFB1 to examine the initial rates of 8,9-dihydro-8-( N 7-guanyl)-9-hydroxyaflatoxin B1 excreted in the urine. Levels of aflatoxin- N 7-guanine adducts in the livers of the Oltipraz-fed animals were reduced 76 and 65% at 2 and 24 h after dosing, respectively. While elimination of total urinary aflatoxins was indistinguishable in the 2 groups, Oltipraz pretreatment led to a 67% reduction in the urinary elimination of aflatoxin- N 7-guanine over the 24-h postdosing period. Protection afforded by Oltipraz against hepatocarcinogenesis induced by AFB1 presumably results from the marked decrease in levels of hepatic DNA adducts. Thus, measurement of integrated levels of aflatoxin- N 7-guanine adducts excreted in the urine may provide a facile, noninvasive, short-term method for monitoring the efficacy of chemoprotection by agents like Oltipraz in individuals at high risk for aflatoxin exposure.
Adrianne E Rogers - One of the best experts on this subject based on the ideXlab platform.
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predictive value of molecular dosimetry individual versus group effects of Oltipraz on aflatoxin albumin adducts and risk of liver cancer
Cancer Epidemiology Biomarkers & Prevention, 1997Co-Authors: Thomas W. Kensler, John D. Groopman, Patricia A. Egner, Adrianne E Rogers, Patrick Dolan, Alvaro Muñoz, Stephen J Gange, Bill D. RoebuckAbstract:Studies in animals and humans have established serum aflatoxin-albumin adducts as biomarkers of exposure to aflatoxin B1 (AFB1), a food-borne hepatocarcinogen. To assess the utility of measurements of aflatoxin-albumin adducts to predict risk of hepatocellular carcinoma (HCC), 123 male F344 rats were dosed with 20 microg of AFB1 daily for 5 weeks after randomization into three groups: no intervention; delayed-transient (500 ppm of Oltipraz, weeks 2 and 3 relative to AFB1); or persistent (500 ppm Oltipraz, weeks -1 to 5). Serial blood samples were collected from each animal at weekly intervals throughout aflatoxin B1 exposure and assayed for levels of aflatoxin-albumin by radioimmune assay. Area under the curve (AUC) values for aflatoxin-albumin adducts decreased 20 and 39% in the delayed-transient and persistent Oltipraz intervention groups, respectively, as compared to no intervention. Similarly, the total incidence of HCC dropped from 83 to 60% (P = 0.03) and 48% (P < 0.01) in these groups. Tumor multiplicity was also reduced in the two Oltipraz intervention groups, whereas time to HCC was increased. Mononuclear cell leukemia, a common neoplasm in F344 rats, was seen in 39% of the control animals, whereas the two Oltipraz interventions reduced incidence to 18% (P = 0.05) and 13% (P = 0.01), respectively. Overall, a significant association was seen between biomarker AUC and risk of HCC (P = 0.01). However, when the predictive value of aflatoxin-albumin adducts was assessed within treatment groups, there was no association between AUC and risk of HCC (P = 0.56). Thus, aflatoxin-albumin adducts can be useful for monitoring population-based changes induced by interventions, such as in chemoprevention trials, but have limited utility in identifying individuals destined to develop HCC. As a consequence, the use of this biomarker in quantitative risk assessment should be pursued cautiously.
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protection against aflatoxin b1 induced hepatocarcinogenesis in f344 rats by 5 2 pyrazinyl 4 methyl 1 2 dithiole 3 thione Oltipraz predictive role for short term molecular dosimetry
Cancer Research, 1991Co-Authors: B D Roebuck, John D. Groopman, Adrianne E Rogers, Thomas W. KenslerAbstract:Previous studies have demonstrated that dietary administration of the schistosomicidal drug 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione (Oltipraz) ameliorates the hepatotoxicity of aflatoxin B1 (AFB1). Notably, mortality, altered hepatic function, hepatic AFB1-DNA adduct levels, and expression of hepatic enzyme-altered foci were markedly reduced in the rat by concurrent feeding of Oltipraz during exposures to AFB1. Collectively, these studies prompted us to evaluate the chemoprotective properties of Oltipraz against AFB1-induced liver cancer. In addition, preliminary molecular dosimetry studies were undertaken to determine the utility of measurements of urinary aflatoxin- N 7-guanine excretion as a marker of relative risk for hepatocarcinogenesis in AFB1-exposed rats. For the carcinogenesis studies, 5-wk-old male F344 rats were randomly divided into two groups. One group (55 rats) received the AIN-76A diet, and the other group (56 rats) received the AIN-76A diet supplemented with 0.075% Oltipraz. The Oltipraz-supplemented diet was fed for 4 wk. Beginning 1 wk after starting the experimental diets, all rats in both groups received 25 µg of AFB1/rat/day by gavage for 5 days per wk over the next 2 wk. One wk following cessation of dosing with AFB1, Oltipraz was removed from the diet, and all rats were fed the AIN-76A diet for the remainder of the experiment. At 3 mo after dosing, livers of ten sentinel rats from each group were analyzed for the burden of γ-glutamyltranspeptidase-positive foci. In accord with previous findings, rats fed the Oltipraz-supplemented diet exhibited substantial reductions in the focal burden (97% reduction; P < 0.05) of these AFB1-induced lesions. The remaining rats were maintained for the cancer study until they became moribund or the termination of the experiment at 23 mo. Gross liver lesions were identified at autopsy and confirmed by microscopic evaluation. An 11% incidence of hepatocellular carcinoma was observed in the AFB1-treated, control diet-fed rats. An additional 9% of this group had hepatocellular adenomas. Oltipraz afforded complete protection against both AFB1-induced hepatocellular neoplasms. Using Kaplan-Meier survival analyses, rats in the Oltipraz group had a significantly ( P < 0.02) longer life span and an increased survival free of liver tumors ( P < 0.0002). Molecular dosimetry studies used rats fed either the Oltipraz-supplemented or control diet for 1 wk and then challenged with a single dose of AFB1 to examine the initial rates of 8,9-dihydro-8-( N 7-guanyl)-9-hydroxyaflatoxin B1 excreted in the urine. Levels of aflatoxin- N 7-guanine adducts in the livers of the Oltipraz-fed animals were reduced 76 and 65% at 2 and 24 h after dosing, respectively. While elimination of total urinary aflatoxins was indistinguishable in the 2 groups, Oltipraz pretreatment led to a 67% reduction in the urinary elimination of aflatoxin- N 7-guanine over the 24-h postdosing period. Protection afforded by Oltipraz against hepatocarcinogenesis induced by AFB1 presumably results from the marked decrease in levels of hepatic DNA adducts. Thus, measurement of integrated levels of aflatoxin- N 7-guanine adducts excreted in the urine may provide a facile, noninvasive, short-term method for monitoring the efficacy of chemoprotection by agents like Oltipraz in individuals at high risk for aflatoxin exposure.
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protection against aflatoxin b1 induced hepatocarcinogenesis in f344 rats by 5 2 pyrazinyl 4 methyl 1 2 dithiole 3 thione Oltipraz predictive role for short term molecular dosimetry
Cancer Research, 1991Co-Authors: Bill D. Roebuck, John D. Groopman, Adrianne E Rogers, Yiliang Liu, Thomas W. KenslerAbstract:Previous studies have demonstrated that dietary administration of the schistosomicidal drug 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione (Oltipraz) ameliorates the hepatotoxicity of aflatoxin B1 (AFB1). Notably, mortality, altered hepatic function, hepatic AFB1-DNA adduct levels, and expression of hepatic enzyme-altered foci were markedly reduced in the rat by concurrent feeding of Oltipraz during exposures to AFB1. Collectively, these studies prompted us to evaluate the chemoprotective properties of Oltipraz against AFB1-induced liver cancer. In addition, preliminary molecular dosimetry studies were undertaken to determine the utility of measurements of urinary aflatoxin-N7-guanine excretion as a marker of relative risk for hepatocarcinogenesis in AFB1-exposed rats. For the carcinogenesis studies, 5-wk-old male F344 rats were randomly divided into two groups. One group (55 rats) received the AIN-76A diet, and the other group (56 rats) received the AIN-76A diet supplemented with 0.075% Oltipraz. The Oltipraz-supplemented diet was fed for 4 wk. Beginning 1 wk after starting the experimental diets, all rats in both groups received 25 micrograms of AFB1/rat/day by gavage for 5 days per wk over the next 2 wk. One wk following cessation of dosing with AFB1, Oltipraz was removed from the diet, and all rats were fed the AIN-76A diet for the remainder of the experiment. At 3 mo after dosing, livers of ten sentinel rats from each group were analyzed for the burden of gamma-glutamyltranspeptidase-positive foci. In accord with previous findings, rats fed the Oltipraz-supplemented diet exhibited substantial reductions in the focal burden (97% reduction; P less than 0.05) of these AFB1-induced lesions. The remaining rats were maintained for the cancer study until they became moribund or the termination of the experiment at 23 mo. Gross liver lesions were identified at autopsy and confirmed by microscopic evaluation. An 11% incidence of hepatocellular carcinoma was observed in the AFB1-treated, control diet-fed rats. An additional 9% of this group had hepatocellular adenomas. Oltipraz afforded complete protection against both AFB1-induced hepatocellular neoplasms. Using Kaplan-Meier survival analyses, rats in the Oltipraz group had a significantly (P less than 0.02) longer life span and an increased survival free of liver tumors (P less than 0.0002). Molecular dosimetry studies used rats fed either the Oltipraz-supplemented or control diet for 1 wk and then challenged with a single dose of AFB1 to examine the initial rates of 8,9-dihydro-8-(N7-guanyl)-9-hydroxyaflatoxin B1 excreted in the urine.(ABSTRACT TRUNCATED AT 400 WORDS)
