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John Digiovanni - One of the best experts on this subject based on the ideXlab platform.
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coumarins are competitive inhibitors of cytochrome p450 1b1 with equal potency for allelic variants
Pharmacogenetics and Genomics, 2005Co-Authors: Jennifer S Mammen, Heather E Kleiner, Thomas R. Sutter, John Digiovanni, Paul T. StricklandAbstract:OBJECTIVES: Coumarins are naturally occurring chemicals with potential as chemopreventive agents, several with known action on the cytochrome P450 1A family. We examined whether cytochrome P450 1B1 (CYP1B1) was inhibited by coumarins, whether such inhibition was competitive, and whether inhibition varied between common polymorphic variants of this enzyme. METHODS: We tested the inhibition properties of four coumarins, bergamottin, Isopimpinellin, isoimperatorin, and imperatorin in an assay for oxidation of (-)benzo[a]pyrene-7R-trans-7,8-dihyrodiol (B[a]P-7,8-diol) by CYP1B1 using yeast-microsome expressed enzymes. These assays were performed with wild-type enzyme and five single-amino acid polymorphic variants. RESULTS: All four coumarins are competitive inhibitors of CYP1B1, with Ki values equal to 587, 11, 6 and 1 muM respectively. Inhibition parameters were consistent between five haplotypes of CYP1B1, three representing common haplotypes in Asians, African-Americans and European-Americans, and two with baseline kinetic parameters previously shown to be potentially different from wild-type. CONCLUSIONS: Coumarins are capable of inhibiting carcinogen activation by CYP1B1 with varying potencies, and their efficacy as chemopreventive agents is not likely to be affected by polymorphism in this enzyme.
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oral administration of the citrus coumarin Isopimpinellin blocks dna adduct formation and skin tumor initiation by 7 12 dimethylbenz a anthracene in sencar mice
Carcinogenesis, 2002Co-Authors: Heather E Kleiner, Suryanarayana V Vulimiri, Melissa J Reed, Matthew F Starost, John DigiovanniAbstract:The current study was designed to evaluate the effects of oral administration of the citrus coumarin, Isopimpinellin, on skin tumor initiation by topically applied benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA). To evaluate the effects of orally administered Isopimpinellin on skin tumor initiation by B[a]P and DMBA, its effects on DNA adduct formation were first evaluated. Female SENCAR mice were pre-treated twice with corn oil, or Isopimpinellin (70 mg/kg body wt per os) at 24 h and 2 h prior to topical treatment with B[a]P or DMBA. Another citrus coumarin, imperatorin, was also included in these experiments for comparison. Orally administered Isopimpinellin and imperatorin significantly inhibited B[a]P-DNA adduct formation by 37 and 26%, respectively. Imperatorin also blocked DMBA-DNA adduct formation by 43%. In a second dose-response study, orally administered Isopimpinellin (35, 70 and 150 mg/kg) blocked DMBA-DNA adduct formation by 23, 56 and 69%, respectively. For the tumor study, mice were pretreated orally with corn oil or Isopimpinellin at 24 and 2 h prior to initiation with DMBA, and 2 weeks later promotion began with 12-O-tetradecanoylphorbol-13-acetate (TPA). Isopimpinellin significantly reduced the mean number of papillomas per mouse by 49, 73 and 78% compared to corn oil controls at 30, 70 and 150 mg/kg body wt, respectively. Orally administered Isopimpinellin also significantly reduced the percentage of mice with papillomas at the highest dose tested (150 mg/kg). The effectiveness of Isopimpinellin given topically over a broad dose range against DMBA tumor initiation was also evaluated for comparison. As part of this study, several parameters of systemic toxicity were evaluated following oral dosing with Isopimpinellin and imperatorin. Mice were treated orally with corn oil, Isopimpinellin or imperatorin (35, 70 and 150 mg/kg body wt per os) once daily for four consecutive days, killed at 24 h after the last dose, and livers, lungs, and kidneys evaluated histologically. In addition, urinary parameters of nephrotoxicity, blood parameters of liver and kidney function, and thrombin clotting time were assayed. No significant changes in blood clotting, or renal or hepatic function were observed. There was, however, a significant increase in liver wt accompanied by cytoplasmic vacuolation of hepatocytes. There were no histopathological changes in lungs or kidneys. Overall, these data indicate that Isopimpinellin (and imperatorin) have chemopreventive effects when administered orally on skin tumor initiation by DMBA.
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role of cytochrome p450 1a1 and 1b1 in the metabolic activation of 7 12 dimethylbenz a anthracene and the effects of naturally occurring furanocoumarins on skin tumor initiation
Chemical Research in Toxicology, 2002Co-Authors: Heather E Kleiner, Suryanarayana V Vulimiri, Melissa J Reed, And Ann Uberecken, John DigiovanniAbstract:The current study was designed to determine the mechanistic basis for differences in the effects of naturally occurring furanocoumarins on skin tumor initiation by 7,12-dimethylbenz[a]anthracene (DMBA). Female SENCAR mice were pretreated topically with bergamottin, imperatorin, or Isopimpinellin (100−3200 nmol), 7,8-benzoflavone (7,8-BF, 5−40 nmol, a known inhibitor of DMBA skin carcinogenesis in mice), or acetone (vehicle control) 5 min prior to topical treatment with DMBA (10 nmol). Imperatorin, Isopimpinellin, and 7,8-BF, but not bergamottin, significantly blocked total DMBA-DNA adduct formation. HPLC analysis of DNA adducts revealed that bergamottin preferentially inhibited formation of anti-DMBA diol-epoxide (DMBADE) derived DNA adducts, imperatorin, and Isopimpinellin inhibited both anti- and syn- derived adducts, whereas 7,8-BF showed some selectivity for reduction of syn-DMBADE-DNA adducts. Mouse embryo fibroblast C3H/10T1/2 (10T1/2) cells, and mouse hepatoma-derived 1c1c7 (Hepa-1) cells, which pr...
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Role of cytochrome P450 1a1 and 1b1 in the metabolic activation of 7,12-dimethylbenz[a]anthracene and the effects of naturally occurring furanocoumarins on skin tumor initiation.
Chemical research in toxicology, 2002Co-Authors: Heather E Kleiner, Suryanarayana V Vulimiri, Melissa J Reed, And Ann Uberecken, John DigiovanniAbstract:The current study was designed to determine the mechanistic basis for differences in the effects of naturally occurring furanocoumarins on skin tumor initiation by 7,12-dimethylbenz[a]anthracene (DMBA). Female SENCAR mice were pretreated topically with bergamottin, imperatorin, or Isopimpinellin (100-3200 nmol), 7,8-benzoflavone (7,8-BF, 5-40 nmol, a known inhibitor of DMBA skin carcinogenesis in mice), or acetone (vehicle control) 5 min prior to topical treatment with DMBA (10 nmol). Imperatorin, Isopimpinellin, and 7,8-BF, but not bergamottin, significantly blocked total DMBA-DNA adduct formation. HPLC analysis of DNA adducts revealed that bergamottin preferentially inhibited formation of anti-DMBA diol-epoxide (DMBADE) derived DNA adducts, imperatorin, and Isopimpinellin inhibited both anti- and syn- derived adducts, whereas 7,8-BF showed some selectivity for reduction of syn-DMBADE-DNA adducts. Mouse embryo fibroblast C3H/10T1/2 (10T1/2) cells, and mouse hepatoma-derived 1c1c7 (Hepa-1) cells, which preferentially express P450 1b1 and P450 1a1, respectively, were co-incubated with 2 microM bergamottin, imperatorin, Isopimpinellin, and 7,8-BF, and with DMBA (2 microM). Hepa-1 cells (P450 1a1) formed mainly anti-DMBADE-DNA adducts. In contrast, 10T1/2 cells (P450 1b1) formed mainly syn-DMBADE-DNA adducts. Bergamottin inhibited DMBA metabolism to DMBA-3,4-diol and blocked DNA adduct formation in Hepa-1 cells, but had little effect in 10T1/2 cells. In contrast, 7,8-BF completely blocked DMBA metabolism and DNA adduct formation in 10T1/2 cells, but had little effect in Hepa-1 cells. Imperatorin and Isopimpinellin inhibited DMBA bioactivation in both cell lines. These results indicate that bergamottin is a more selective inhibitor of P450 1a1 and overall a less effective inhibitor of the metabolic activation of DMBA in mouse epidermis. In contrast, imperatorin, Isopimpinellin, and especially 7,8-BF, which block metabolic activation of DMBA in mouse epidermis, appear more selective for P450 1b1. On the basis of our studies using 10T1/2 cells and Hepa-1 cells, it appears that P450 1a1 is primarily responsible for converting DMBA-3,4-diol to anti-DMBADE, whereas P450 1b1 is primarily responsible for converting DMBA-3,4-diol to syn-DMBADE. These data demonstrate the role of P450 1a1 and 1b1 in the metabolic activation of DMBA in mouse epidermis and provide a mechanistic explanation for the differential effects of naturally occurring furanocoumarins (and 7,8-BF) on polycyclic aromatic hydrocarbon skin carcinogenesis.
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Inhibition and inactivation of murine hepatic ethoxy- and pentoxyresorufin O-dealkylase by naturally occurring coumarins.
Chemical research in toxicology, 1993Co-Authors: Yingna Cai, Mike J. Ashwood-smith, Daniel Bennett, Raghunathan V. Nair, Oluna Ceska, John DigiovanniAbstract:The present study was designed to evaluate the effects of a series of natural coumarins on ethoxyresorufin O-dealkylase (EROD) and pentoxyresorufin O-dealkylase (PROD) activities in vitro using hepatic tissues from SENCAR mice. Fifteen different coumarins were examined for potential modulating activities. Several naturally occurring coumarins, found in the human diet, were effective inhibitors of hepatic EROD activity in vitro, including coriandrin, bergamottin, isoimperatorin, and ostruthin. Notably, coriandrin and bergamottin were approximately as potent as 7,8-benzoflavone, a relatively selective inhibitor of cytochrome P450 1A1. Several naturally occurring coumarins were also potent inhibitors of hepatic PROD activity, including imperatorin, bergamottin, Isopimpinellin, and angelicin. Kinetic studies of the type of inhibition revealed that these compounds inhibited hepatic EROD and PROD activity by a variety of modes rather than by a uniform one. Furthermore, experiments using a two-stage incubation assay revealed that coriandrin, imperatorin, ostruthin, and several other natural coumarins inactivated hepatic EROD activity (i.e., predominantly cytochrome P450 1A1-mediated) and that Isopimpinellin inactivated hepatic PROD activity (i.e., predominantly cytochrome P450 2B1-mediated). Finally, the results indicate that some coumarins had selective inhibitory effects for EROD vs PROD and preliminary analyses suggested a possible structural basis for the observed differences. The current data suggest that certain naturally occurring coumarins, to which humans are exposed in the diet, are potent modulators of cytochrome P450. Furthermore, these compounds may be capable of influencing the metabolic activation of other xenobiotics, including chemical carcinogens.
Heather E Kleiner - One of the best experts on this subject based on the ideXlab platform.
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coumarins are competitive inhibitors of cytochrome p450 1b1 with equal potency for allelic variants
Pharmacogenetics and Genomics, 2005Co-Authors: Jennifer S Mammen, Heather E Kleiner, Thomas R. Sutter, John Digiovanni, Paul T. StricklandAbstract:OBJECTIVES: Coumarins are naturally occurring chemicals with potential as chemopreventive agents, several with known action on the cytochrome P450 1A family. We examined whether cytochrome P450 1B1 (CYP1B1) was inhibited by coumarins, whether such inhibition was competitive, and whether inhibition varied between common polymorphic variants of this enzyme. METHODS: We tested the inhibition properties of four coumarins, bergamottin, Isopimpinellin, isoimperatorin, and imperatorin in an assay for oxidation of (-)benzo[a]pyrene-7R-trans-7,8-dihyrodiol (B[a]P-7,8-diol) by CYP1B1 using yeast-microsome expressed enzymes. These assays were performed with wild-type enzyme and five single-amino acid polymorphic variants. RESULTS: All four coumarins are competitive inhibitors of CYP1B1, with Ki values equal to 587, 11, 6 and 1 muM respectively. Inhibition parameters were consistent between five haplotypes of CYP1B1, three representing common haplotypes in Asians, African-Americans and European-Americans, and two with baseline kinetic parameters previously shown to be potentially different from wild-type. CONCLUSIONS: Coumarins are capable of inhibiting carcinogen activation by CYP1B1 with varying potencies, and their efficacy as chemopreventive agents is not likely to be affected by polymorphism in this enzyme.
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oral administration of the citrus coumarin Isopimpinellin blocks dna adduct formation and skin tumor initiation by 7 12 dimethylbenz a anthracene in sencar mice
Carcinogenesis, 2002Co-Authors: Heather E Kleiner, Suryanarayana V Vulimiri, Melissa J Reed, Matthew F Starost, John DigiovanniAbstract:The current study was designed to evaluate the effects of oral administration of the citrus coumarin, Isopimpinellin, on skin tumor initiation by topically applied benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA). To evaluate the effects of orally administered Isopimpinellin on skin tumor initiation by B[a]P and DMBA, its effects on DNA adduct formation were first evaluated. Female SENCAR mice were pre-treated twice with corn oil, or Isopimpinellin (70 mg/kg body wt per os) at 24 h and 2 h prior to topical treatment with B[a]P or DMBA. Another citrus coumarin, imperatorin, was also included in these experiments for comparison. Orally administered Isopimpinellin and imperatorin significantly inhibited B[a]P-DNA adduct formation by 37 and 26%, respectively. Imperatorin also blocked DMBA-DNA adduct formation by 43%. In a second dose-response study, orally administered Isopimpinellin (35, 70 and 150 mg/kg) blocked DMBA-DNA adduct formation by 23, 56 and 69%, respectively. For the tumor study, mice were pretreated orally with corn oil or Isopimpinellin at 24 and 2 h prior to initiation with DMBA, and 2 weeks later promotion began with 12-O-tetradecanoylphorbol-13-acetate (TPA). Isopimpinellin significantly reduced the mean number of papillomas per mouse by 49, 73 and 78% compared to corn oil controls at 30, 70 and 150 mg/kg body wt, respectively. Orally administered Isopimpinellin also significantly reduced the percentage of mice with papillomas at the highest dose tested (150 mg/kg). The effectiveness of Isopimpinellin given topically over a broad dose range against DMBA tumor initiation was also evaluated for comparison. As part of this study, several parameters of systemic toxicity were evaluated following oral dosing with Isopimpinellin and imperatorin. Mice were treated orally with corn oil, Isopimpinellin or imperatorin (35, 70 and 150 mg/kg body wt per os) once daily for four consecutive days, killed at 24 h after the last dose, and livers, lungs, and kidneys evaluated histologically. In addition, urinary parameters of nephrotoxicity, blood parameters of liver and kidney function, and thrombin clotting time were assayed. No significant changes in blood clotting, or renal or hepatic function were observed. There was, however, a significant increase in liver wt accompanied by cytoplasmic vacuolation of hepatocytes. There were no histopathological changes in lungs or kidneys. Overall, these data indicate that Isopimpinellin (and imperatorin) have chemopreventive effects when administered orally on skin tumor initiation by DMBA.
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role of cytochrome p450 1a1 and 1b1 in the metabolic activation of 7 12 dimethylbenz a anthracene and the effects of naturally occurring furanocoumarins on skin tumor initiation
Chemical Research in Toxicology, 2002Co-Authors: Heather E Kleiner, Suryanarayana V Vulimiri, Melissa J Reed, And Ann Uberecken, John DigiovanniAbstract:The current study was designed to determine the mechanistic basis for differences in the effects of naturally occurring furanocoumarins on skin tumor initiation by 7,12-dimethylbenz[a]anthracene (DMBA). Female SENCAR mice were pretreated topically with bergamottin, imperatorin, or Isopimpinellin (100−3200 nmol), 7,8-benzoflavone (7,8-BF, 5−40 nmol, a known inhibitor of DMBA skin carcinogenesis in mice), or acetone (vehicle control) 5 min prior to topical treatment with DMBA (10 nmol). Imperatorin, Isopimpinellin, and 7,8-BF, but not bergamottin, significantly blocked total DMBA-DNA adduct formation. HPLC analysis of DNA adducts revealed that bergamottin preferentially inhibited formation of anti-DMBA diol-epoxide (DMBADE) derived DNA adducts, imperatorin, and Isopimpinellin inhibited both anti- and syn- derived adducts, whereas 7,8-BF showed some selectivity for reduction of syn-DMBADE-DNA adducts. Mouse embryo fibroblast C3H/10T1/2 (10T1/2) cells, and mouse hepatoma-derived 1c1c7 (Hepa-1) cells, which pr...
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Role of cytochrome P450 1a1 and 1b1 in the metabolic activation of 7,12-dimethylbenz[a]anthracene and the effects of naturally occurring furanocoumarins on skin tumor initiation.
Chemical research in toxicology, 2002Co-Authors: Heather E Kleiner, Suryanarayana V Vulimiri, Melissa J Reed, And Ann Uberecken, John DigiovanniAbstract:The current study was designed to determine the mechanistic basis for differences in the effects of naturally occurring furanocoumarins on skin tumor initiation by 7,12-dimethylbenz[a]anthracene (DMBA). Female SENCAR mice were pretreated topically with bergamottin, imperatorin, or Isopimpinellin (100-3200 nmol), 7,8-benzoflavone (7,8-BF, 5-40 nmol, a known inhibitor of DMBA skin carcinogenesis in mice), or acetone (vehicle control) 5 min prior to topical treatment with DMBA (10 nmol). Imperatorin, Isopimpinellin, and 7,8-BF, but not bergamottin, significantly blocked total DMBA-DNA adduct formation. HPLC analysis of DNA adducts revealed that bergamottin preferentially inhibited formation of anti-DMBA diol-epoxide (DMBADE) derived DNA adducts, imperatorin, and Isopimpinellin inhibited both anti- and syn- derived adducts, whereas 7,8-BF showed some selectivity for reduction of syn-DMBADE-DNA adducts. Mouse embryo fibroblast C3H/10T1/2 (10T1/2) cells, and mouse hepatoma-derived 1c1c7 (Hepa-1) cells, which preferentially express P450 1b1 and P450 1a1, respectively, were co-incubated with 2 microM bergamottin, imperatorin, Isopimpinellin, and 7,8-BF, and with DMBA (2 microM). Hepa-1 cells (P450 1a1) formed mainly anti-DMBADE-DNA adducts. In contrast, 10T1/2 cells (P450 1b1) formed mainly syn-DMBADE-DNA adducts. Bergamottin inhibited DMBA metabolism to DMBA-3,4-diol and blocked DNA adduct formation in Hepa-1 cells, but had little effect in 10T1/2 cells. In contrast, 7,8-BF completely blocked DMBA metabolism and DNA adduct formation in 10T1/2 cells, but had little effect in Hepa-1 cells. Imperatorin and Isopimpinellin inhibited DMBA bioactivation in both cell lines. These results indicate that bergamottin is a more selective inhibitor of P450 1a1 and overall a less effective inhibitor of the metabolic activation of DMBA in mouse epidermis. In contrast, imperatorin, Isopimpinellin, and especially 7,8-BF, which block metabolic activation of DMBA in mouse epidermis, appear more selective for P450 1b1. On the basis of our studies using 10T1/2 cells and Hepa-1 cells, it appears that P450 1a1 is primarily responsible for converting DMBA-3,4-diol to anti-DMBADE, whereas P450 1b1 is primarily responsible for converting DMBA-3,4-diol to syn-DMBADE. These data demonstrate the role of P450 1a1 and 1b1 in the metabolic activation of DMBA in mouse epidermis and provide a mechanistic explanation for the differential effects of naturally occurring furanocoumarins (and 7,8-BF) on polycyclic aromatic hydrocarbon skin carcinogenesis.
Melissa J Reed - One of the best experts on this subject based on the ideXlab platform.
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oral administration of the citrus coumarin Isopimpinellin blocks dna adduct formation and skin tumor initiation by 7 12 dimethylbenz a anthracene in sencar mice
Carcinogenesis, 2002Co-Authors: Heather E Kleiner, Suryanarayana V Vulimiri, Melissa J Reed, Matthew F Starost, John DigiovanniAbstract:The current study was designed to evaluate the effects of oral administration of the citrus coumarin, Isopimpinellin, on skin tumor initiation by topically applied benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA). To evaluate the effects of orally administered Isopimpinellin on skin tumor initiation by B[a]P and DMBA, its effects on DNA adduct formation were first evaluated. Female SENCAR mice were pre-treated twice with corn oil, or Isopimpinellin (70 mg/kg body wt per os) at 24 h and 2 h prior to topical treatment with B[a]P or DMBA. Another citrus coumarin, imperatorin, was also included in these experiments for comparison. Orally administered Isopimpinellin and imperatorin significantly inhibited B[a]P-DNA adduct formation by 37 and 26%, respectively. Imperatorin also blocked DMBA-DNA adduct formation by 43%. In a second dose-response study, orally administered Isopimpinellin (35, 70 and 150 mg/kg) blocked DMBA-DNA adduct formation by 23, 56 and 69%, respectively. For the tumor study, mice were pretreated orally with corn oil or Isopimpinellin at 24 and 2 h prior to initiation with DMBA, and 2 weeks later promotion began with 12-O-tetradecanoylphorbol-13-acetate (TPA). Isopimpinellin significantly reduced the mean number of papillomas per mouse by 49, 73 and 78% compared to corn oil controls at 30, 70 and 150 mg/kg body wt, respectively. Orally administered Isopimpinellin also significantly reduced the percentage of mice with papillomas at the highest dose tested (150 mg/kg). The effectiveness of Isopimpinellin given topically over a broad dose range against DMBA tumor initiation was also evaluated for comparison. As part of this study, several parameters of systemic toxicity were evaluated following oral dosing with Isopimpinellin and imperatorin. Mice were treated orally with corn oil, Isopimpinellin or imperatorin (35, 70 and 150 mg/kg body wt per os) once daily for four consecutive days, killed at 24 h after the last dose, and livers, lungs, and kidneys evaluated histologically. In addition, urinary parameters of nephrotoxicity, blood parameters of liver and kidney function, and thrombin clotting time were assayed. No significant changes in blood clotting, or renal or hepatic function were observed. There was, however, a significant increase in liver wt accompanied by cytoplasmic vacuolation of hepatocytes. There were no histopathological changes in lungs or kidneys. Overall, these data indicate that Isopimpinellin (and imperatorin) have chemopreventive effects when administered orally on skin tumor initiation by DMBA.
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role of cytochrome p450 1a1 and 1b1 in the metabolic activation of 7 12 dimethylbenz a anthracene and the effects of naturally occurring furanocoumarins on skin tumor initiation
Chemical Research in Toxicology, 2002Co-Authors: Heather E Kleiner, Suryanarayana V Vulimiri, Melissa J Reed, And Ann Uberecken, John DigiovanniAbstract:The current study was designed to determine the mechanistic basis for differences in the effects of naturally occurring furanocoumarins on skin tumor initiation by 7,12-dimethylbenz[a]anthracene (DMBA). Female SENCAR mice were pretreated topically with bergamottin, imperatorin, or Isopimpinellin (100−3200 nmol), 7,8-benzoflavone (7,8-BF, 5−40 nmol, a known inhibitor of DMBA skin carcinogenesis in mice), or acetone (vehicle control) 5 min prior to topical treatment with DMBA (10 nmol). Imperatorin, Isopimpinellin, and 7,8-BF, but not bergamottin, significantly blocked total DMBA-DNA adduct formation. HPLC analysis of DNA adducts revealed that bergamottin preferentially inhibited formation of anti-DMBA diol-epoxide (DMBADE) derived DNA adducts, imperatorin, and Isopimpinellin inhibited both anti- and syn- derived adducts, whereas 7,8-BF showed some selectivity for reduction of syn-DMBADE-DNA adducts. Mouse embryo fibroblast C3H/10T1/2 (10T1/2) cells, and mouse hepatoma-derived 1c1c7 (Hepa-1) cells, which pr...
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Role of cytochrome P450 1a1 and 1b1 in the metabolic activation of 7,12-dimethylbenz[a]anthracene and the effects of naturally occurring furanocoumarins on skin tumor initiation.
Chemical research in toxicology, 2002Co-Authors: Heather E Kleiner, Suryanarayana V Vulimiri, Melissa J Reed, And Ann Uberecken, John DigiovanniAbstract:The current study was designed to determine the mechanistic basis for differences in the effects of naturally occurring furanocoumarins on skin tumor initiation by 7,12-dimethylbenz[a]anthracene (DMBA). Female SENCAR mice were pretreated topically with bergamottin, imperatorin, or Isopimpinellin (100-3200 nmol), 7,8-benzoflavone (7,8-BF, 5-40 nmol, a known inhibitor of DMBA skin carcinogenesis in mice), or acetone (vehicle control) 5 min prior to topical treatment with DMBA (10 nmol). Imperatorin, Isopimpinellin, and 7,8-BF, but not bergamottin, significantly blocked total DMBA-DNA adduct formation. HPLC analysis of DNA adducts revealed that bergamottin preferentially inhibited formation of anti-DMBA diol-epoxide (DMBADE) derived DNA adducts, imperatorin, and Isopimpinellin inhibited both anti- and syn- derived adducts, whereas 7,8-BF showed some selectivity for reduction of syn-DMBADE-DNA adducts. Mouse embryo fibroblast C3H/10T1/2 (10T1/2) cells, and mouse hepatoma-derived 1c1c7 (Hepa-1) cells, which preferentially express P450 1b1 and P450 1a1, respectively, were co-incubated with 2 microM bergamottin, imperatorin, Isopimpinellin, and 7,8-BF, and with DMBA (2 microM). Hepa-1 cells (P450 1a1) formed mainly anti-DMBADE-DNA adducts. In contrast, 10T1/2 cells (P450 1b1) formed mainly syn-DMBADE-DNA adducts. Bergamottin inhibited DMBA metabolism to DMBA-3,4-diol and blocked DNA adduct formation in Hepa-1 cells, but had little effect in 10T1/2 cells. In contrast, 7,8-BF completely blocked DMBA metabolism and DNA adduct formation in 10T1/2 cells, but had little effect in Hepa-1 cells. Imperatorin and Isopimpinellin inhibited DMBA bioactivation in both cell lines. These results indicate that bergamottin is a more selective inhibitor of P450 1a1 and overall a less effective inhibitor of the metabolic activation of DMBA in mouse epidermis. In contrast, imperatorin, Isopimpinellin, and especially 7,8-BF, which block metabolic activation of DMBA in mouse epidermis, appear more selective for P450 1b1. On the basis of our studies using 10T1/2 cells and Hepa-1 cells, it appears that P450 1a1 is primarily responsible for converting DMBA-3,4-diol to anti-DMBADE, whereas P450 1b1 is primarily responsible for converting DMBA-3,4-diol to syn-DMBADE. These data demonstrate the role of P450 1a1 and 1b1 in the metabolic activation of DMBA in mouse epidermis and provide a mechanistic explanation for the differential effects of naturally occurring furanocoumarins (and 7,8-BF) on polycyclic aromatic hydrocarbon skin carcinogenesis.
Suryanarayana V Vulimiri - One of the best experts on this subject based on the ideXlab platform.
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oral administration of the citrus coumarin Isopimpinellin blocks dna adduct formation and skin tumor initiation by 7 12 dimethylbenz a anthracene in sencar mice
Carcinogenesis, 2002Co-Authors: Heather E Kleiner, Suryanarayana V Vulimiri, Melissa J Reed, Matthew F Starost, John DigiovanniAbstract:The current study was designed to evaluate the effects of oral administration of the citrus coumarin, Isopimpinellin, on skin tumor initiation by topically applied benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA). To evaluate the effects of orally administered Isopimpinellin on skin tumor initiation by B[a]P and DMBA, its effects on DNA adduct formation were first evaluated. Female SENCAR mice were pre-treated twice with corn oil, or Isopimpinellin (70 mg/kg body wt per os) at 24 h and 2 h prior to topical treatment with B[a]P or DMBA. Another citrus coumarin, imperatorin, was also included in these experiments for comparison. Orally administered Isopimpinellin and imperatorin significantly inhibited B[a]P-DNA adduct formation by 37 and 26%, respectively. Imperatorin also blocked DMBA-DNA adduct formation by 43%. In a second dose-response study, orally administered Isopimpinellin (35, 70 and 150 mg/kg) blocked DMBA-DNA adduct formation by 23, 56 and 69%, respectively. For the tumor study, mice were pretreated orally with corn oil or Isopimpinellin at 24 and 2 h prior to initiation with DMBA, and 2 weeks later promotion began with 12-O-tetradecanoylphorbol-13-acetate (TPA). Isopimpinellin significantly reduced the mean number of papillomas per mouse by 49, 73 and 78% compared to corn oil controls at 30, 70 and 150 mg/kg body wt, respectively. Orally administered Isopimpinellin also significantly reduced the percentage of mice with papillomas at the highest dose tested (150 mg/kg). The effectiveness of Isopimpinellin given topically over a broad dose range against DMBA tumor initiation was also evaluated for comparison. As part of this study, several parameters of systemic toxicity were evaluated following oral dosing with Isopimpinellin and imperatorin. Mice were treated orally with corn oil, Isopimpinellin or imperatorin (35, 70 and 150 mg/kg body wt per os) once daily for four consecutive days, killed at 24 h after the last dose, and livers, lungs, and kidneys evaluated histologically. In addition, urinary parameters of nephrotoxicity, blood parameters of liver and kidney function, and thrombin clotting time were assayed. No significant changes in blood clotting, or renal or hepatic function were observed. There was, however, a significant increase in liver wt accompanied by cytoplasmic vacuolation of hepatocytes. There were no histopathological changes in lungs or kidneys. Overall, these data indicate that Isopimpinellin (and imperatorin) have chemopreventive effects when administered orally on skin tumor initiation by DMBA.
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role of cytochrome p450 1a1 and 1b1 in the metabolic activation of 7 12 dimethylbenz a anthracene and the effects of naturally occurring furanocoumarins on skin tumor initiation
Chemical Research in Toxicology, 2002Co-Authors: Heather E Kleiner, Suryanarayana V Vulimiri, Melissa J Reed, And Ann Uberecken, John DigiovanniAbstract:The current study was designed to determine the mechanistic basis for differences in the effects of naturally occurring furanocoumarins on skin tumor initiation by 7,12-dimethylbenz[a]anthracene (DMBA). Female SENCAR mice were pretreated topically with bergamottin, imperatorin, or Isopimpinellin (100−3200 nmol), 7,8-benzoflavone (7,8-BF, 5−40 nmol, a known inhibitor of DMBA skin carcinogenesis in mice), or acetone (vehicle control) 5 min prior to topical treatment with DMBA (10 nmol). Imperatorin, Isopimpinellin, and 7,8-BF, but not bergamottin, significantly blocked total DMBA-DNA adduct formation. HPLC analysis of DNA adducts revealed that bergamottin preferentially inhibited formation of anti-DMBA diol-epoxide (DMBADE) derived DNA adducts, imperatorin, and Isopimpinellin inhibited both anti- and syn- derived adducts, whereas 7,8-BF showed some selectivity for reduction of syn-DMBADE-DNA adducts. Mouse embryo fibroblast C3H/10T1/2 (10T1/2) cells, and mouse hepatoma-derived 1c1c7 (Hepa-1) cells, which pr...
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Role of cytochrome P450 1a1 and 1b1 in the metabolic activation of 7,12-dimethylbenz[a]anthracene and the effects of naturally occurring furanocoumarins on skin tumor initiation.
Chemical research in toxicology, 2002Co-Authors: Heather E Kleiner, Suryanarayana V Vulimiri, Melissa J Reed, And Ann Uberecken, John DigiovanniAbstract:The current study was designed to determine the mechanistic basis for differences in the effects of naturally occurring furanocoumarins on skin tumor initiation by 7,12-dimethylbenz[a]anthracene (DMBA). Female SENCAR mice were pretreated topically with bergamottin, imperatorin, or Isopimpinellin (100-3200 nmol), 7,8-benzoflavone (7,8-BF, 5-40 nmol, a known inhibitor of DMBA skin carcinogenesis in mice), or acetone (vehicle control) 5 min prior to topical treatment with DMBA (10 nmol). Imperatorin, Isopimpinellin, and 7,8-BF, but not bergamottin, significantly blocked total DMBA-DNA adduct formation. HPLC analysis of DNA adducts revealed that bergamottin preferentially inhibited formation of anti-DMBA diol-epoxide (DMBADE) derived DNA adducts, imperatorin, and Isopimpinellin inhibited both anti- and syn- derived adducts, whereas 7,8-BF showed some selectivity for reduction of syn-DMBADE-DNA adducts. Mouse embryo fibroblast C3H/10T1/2 (10T1/2) cells, and mouse hepatoma-derived 1c1c7 (Hepa-1) cells, which preferentially express P450 1b1 and P450 1a1, respectively, were co-incubated with 2 microM bergamottin, imperatorin, Isopimpinellin, and 7,8-BF, and with DMBA (2 microM). Hepa-1 cells (P450 1a1) formed mainly anti-DMBADE-DNA adducts. In contrast, 10T1/2 cells (P450 1b1) formed mainly syn-DMBADE-DNA adducts. Bergamottin inhibited DMBA metabolism to DMBA-3,4-diol and blocked DNA adduct formation in Hepa-1 cells, but had little effect in 10T1/2 cells. In contrast, 7,8-BF completely blocked DMBA metabolism and DNA adduct formation in 10T1/2 cells, but had little effect in Hepa-1 cells. Imperatorin and Isopimpinellin inhibited DMBA bioactivation in both cell lines. These results indicate that bergamottin is a more selective inhibitor of P450 1a1 and overall a less effective inhibitor of the metabolic activation of DMBA in mouse epidermis. In contrast, imperatorin, Isopimpinellin, and especially 7,8-BF, which block metabolic activation of DMBA in mouse epidermis, appear more selective for P450 1b1. On the basis of our studies using 10T1/2 cells and Hepa-1 cells, it appears that P450 1a1 is primarily responsible for converting DMBA-3,4-diol to anti-DMBADE, whereas P450 1b1 is primarily responsible for converting DMBA-3,4-diol to syn-DMBADE. These data demonstrate the role of P450 1a1 and 1b1 in the metabolic activation of DMBA in mouse epidermis and provide a mechanistic explanation for the differential effects of naturally occurring furanocoumarins (and 7,8-BF) on polycyclic aromatic hydrocarbon skin carcinogenesis.
Frédéric Bourgaud - One of the best experts on this subject based on the ideXlab platform.
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Schematic representation of the coumarin and furanocoumarin pathways.
2015Co-Authors: Audray Dugrand-judek, Alexandre Olry, Alain Hehn, Gilles Costantino, Patrick Ollitrault, Yann Froelicher, Frédéric BourgaudAbstract:Solid lines indicate direct enzymatic steps; dashed lines represent multiple enzymatic steps. Coumarins are framed in orange, furanocoumarins of the bergapten cluster are framed in blue, furanocoumarins of the xanthotoxin cluster are framed in red, and furanocoumarins of the Isopimpinellin cluster are framed in green.
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Heatmap displaying the coumarin and furanocoumarin profiles in the pulp of the 61 Citrus species investigated.
2015Co-Authors: Audray Dugrand-judek, Alexandre Olry, Alain Hehn, Gilles Costantino, Patrick Ollitrault, Yann Froelicher, Frédéric BourgaudAbstract:A: heatmap; B: dendrogram of compounds; C: dendrogram of Citrus varieties. A red square highlights the presence of a given compound, while a yellow square shows its absence. Coumarins are represented in orange; furanocoumarins of the bergapten cluster, in blue; furanocoumarins of the xanthotoxin cluster, in red; and furanocoumarins of the Isopimpinellin cluster, in green.
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Heatmap displaying the coumarin and furanocoumarin profiles in the peel of the 61 Citrus species investigated.
2015Co-Authors: Audray Dugrand-judek, Alexandre Olry, Alain Hehn, Gilles Costantino, Patrick Ollitrault, Yann Froelicher, Frédéric BourgaudAbstract:A: heatmap; B: dendrogram of compounds; C: dendrogram of Citrus varieties. A red square highlights the presence of a given compound, while a yellow square shows its absence. Coumarins are represented in orange; furanocoumarins of the bergapten cluster, in blue; furanocoumarins of the xanthotoxin cluster, in red; and furanocoumarins of the Isopimpinellin cluster, in green.
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Coumarin and furanocoumarin quantities (mmol kg-1 fresh weight) in the pulp extracts of the 61 Citrus species investigated.
2015Co-Authors: Audray Dugrand-judek, Alexandre Olry, Alain Hehn, Gilles Costantino, Patrick Ollitrault, Yann Froelicher, Frédéric BourgaudAbstract:Coumarins are represented in orange; furanocoumarins of the bergapten cluster, in blue; furanocoumarins of the xanthotoxin cluster, in red; and furanocoumarins of the Isopimpinellin cluster, in green. Ancestral taxa and secondary species are highlighted in the bottom of the graph. Sweet mandarins are presented in bright red, and acidic mandarins are illustrated in deep red.
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Coumarin and furanocoumarin quantities (mmol kg-1 fresh weight) in the peel extracts of the 61 Citrus species investigated.
2015Co-Authors: Audray Dugrand-judek, Alexandre Olry, Alain Hehn, Gilles Costantino, Patrick Ollitrault, Yann Froelicher, Frédéric BourgaudAbstract:Coumarins are represented in orange; furanocoumarins of the bergapten cluster, in blue; furanocoumarins of the xanthotoxin cluster, in red; and furanocoumarins of the Isopimpinellin cluster, in green. Ancestral taxa and secondary species are highlighted in the bottom of the graph. Sweet mandarins are presented in bright red, and acidic mandarins are illustrated in deep red.
