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1 Aminobenzotriazole

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Garth Jones – One of the best experts on this subject based on the ideXlab platform.

Kazuhide Iwasaki – One of the best experts on this subject based on the ideXlab platform.

  • In vitro inhibitory effect of 1Aminobenzotriazole on drug oxidations in human liver microsomes: a comparison with SKF-525A.
    Drug metabolism and pharmacokinetics, 2005
    Co-Authors: Chie Emoto, Shigeo Murase, Yasufusa Sawada, Kazuhide Iwasaki

    Summary: 1Aminobenzotriazole (ABT) is extensively used as a non-specific cytochrome P450 (CYP) inhibitor. In this study, the inhibitory effect of ABT on CYP-dependent drug oxidations was investigated in human liver microsomes (HLM) and compared with that of SKF-525A, another non-specific inhibitor. The following probe activities for human CYP isoforms were determined using pooled HLM: phenacetin O-deethylation (CYP1A2); diclofenac 4′-hydroxylation (CYP2C9); S-mephenytoin 4′-hydroxylation, (CYP2C19); bufuralol 1‘-hydroxylation (CYP2D6); chlorzoxazone 6-hydroxylation (CYP2E1); midazolam 1‘-hydroxylation, nifedipine oxidation, and testosterone 6 β -hydroxylation (CYP3A). ABT had the strongest inhibitory effect on the CYP3A-dependent drug oxidations and the weakest effect on the diclofenac 4′-hydroxylation. SKF-525A potently inhibited the bufuralol 1‘-hydroxylation, but weakly inhibited chlorzoxazone 6-hydroxylation. The inhibitory effects of ABT and SKF-525A were increased by preincubation in some probe reactions, and this preincubation effect was greater in ABT than in SKF-525A. The remarkable IC 50 shift (> 10 times) by preincubation with ABT was observed on the phenacetin O-deethylation, chlorzoxazone 6-hydroxylation, and midazolam 1‘-hydroxylation. In conclusion, ABT and SKF-525A had a wide range of IC 50 values in inhibiting the drug oxidations by HLM with and without preincubation.

  • In Vitro Inhibitory Effect of 1Aminobenzotriazole on Drug Oxidations Catalyzed by Human Cytochrome P450 Enzymes: A Comparison with SKF-525A and Ketoconazole
    Drug metabolism and pharmacokinetics, 2003
    Co-Authors: Chie Emoto, Shigeo Murase, Yasufusa Sawada, Barry Jones, Kazuhide Iwasaki

    1Aminobenzotriazole (ABT) is widely used as a non-specific inhibitor of animal cytochrome P450 (CYP). In the present study, the inhibitory effect of ABT was investigated on drug oxidations catalyzed by human CYP isoforms. This inhibitory effect was compared with that of SKF-525A, another non-specific inhibitor, and ketoconazole, a potent inhibitor of CYP3A. Bacurovirus-expressed recombinant human CYP isoforms were used as an enzyme source. The specific activities for human CYP isoforms are: phenacetin O-deethylation, for CYP1A2; diclofenac 4′-hydroxylation, for CYP2C9; S-mephenytoin 4′-hydroxylation, for CYP2C19; bufuralol 1‘-hydroxylation, for CYP2D6; chlorzoxazone 6-hydroxylation, for CYP2E1; testosterone 6beta-hydroxylation, nifedipine oxidation, and midazolam 1‘-hydroxylation, for CYP3A4. ABT inhibited both CYP1A2-dependent activity (Ki=330 microM) and CYP2E1-dependent activity (Ki=8.7 microM). In contrast, SKF-525A weakly inhibited CYP1A2-dependent activities (46% inhibition at 1200 microM) and CYP2E1-dependent activities (65% inhibition at 1000 microM). ABT exhibited the highest Ki value for CYP2C9-dependent diclofenac 4′-hydroxylation among those determined by this assay (Ki=3500 microM). Moreover, SKF-525A showed strong inhibition of CYP2D6-dependent bufuralol 1‘-hydroxylation (Ki=0.043 microM). Ketoconazole inhibited all tested drug oxidations, however, its inhibitory effect on CYP1A2-dependent activities was very weak (50% inhibition at 120 microM). ABT, SKF-525A, and ketoconazole showed different selectivity and had a wide range of Ki values for the drug oxidations catalyzed by human CYP enzymes. Therefore, we conclude that inhibitory studies designed to predict the contribution of CYP enzymes to the metabolism of certain compounds should be performed using multiple CYP inhibitors, such as ABT, SKF-525A, and ketoconazole.

Joseph A. Carcillo – One of the best experts on this subject based on the ideXlab platform.

Howard D. Colby – One of the best experts on this subject based on the ideXlab platform.

  • Inhibition of Testicular Steroid Metabolism by Administration of 1Aminobenzotriazole to Rats
    Pharmacology, 1998
    Co-Authors: Michael Soltis, Howard D. Colby

    Effects of 1Aminobenzotriazole (ABT) on testicular steroid metametabolism were evaluated in rats. Administration of ABT to adult male rats caused dose-dependent decreases in testicular microsomal and mitochondrial cytochrome P450 concentrations. Significant losses of P450 occurred within 8 h of ABT treatment. Accompanying the declines in testicular P450 content were decreases in microsomal 17 alpha-hydroxylase and mitochondrial cholesterol sidechain cleavage activities. Incubation of testicular microsomes or mitochondria in vitro with ABT plus an NADPH-generating system had no effect on P450 concentrations or on rates of steroid metametabolism. By contrast, incubation of hepatic microsomes with ABT under the same conditions decreased P450 levels and xenobiotic-metabolizing activity. The results indicate that ABT in vivo causes inactivation of steroidogenic P450 isozymes in the testis, but the mechanism of inactivation differs from that on xenobiotic-metabolizing isozymes.

  • Inhibition of adrenal steroid metabolism by administration of 1Aminobenzotriazole to guinea pigs
    The Journal of Steroid Biochemistry and Molecular Biology, 1995
    Co-Authors: Jeffrey M. Voigt, Bruce A. Mico, Howard D. Colby

    Abstract Prior in vitro investigations demonstrated that the P 450 suicide substrate, 1Aminobenzotriazole (ABT), was a potent inhibitor of xenobiotic metabolism but had no effect on steroidogenic enzymes in the guinea pig adrenal cortex. Studies were done to determine if ABT administration to guinea pigs in vivo also selectively inhibited adrenal xenobiotic metabolism. At single doses of 25 or 50 mg/kg, ABT effected rapid decreases in spectrally detectable adrenal P 450 concentrations. The higher dose caused approx. 75% decreases in microsomal and mitochondrial P 450 levels within 2 h. The decreases in P 450 were sustained for 24 h but concentrations returned to control levels within 72 h. Accompanying the ABT-induced decreases in adrenal P 450 content were proportionately similar decreases in P 450-mediated xenobiotic and steroid metametabolism. Microsomal benzo(a)pyrene hydroxylase, benzphetamine N -demethylase, 17α-hydroxylase and 21-hydroxylase activities were decreased to 20–25% of control values by the higher dose of ABT. Mitochondrial 11β-hydroxylase and cholesterol sidechain cleavage activities were similarly diminished by ABT treatment. Adrenal 3β-hydroxysteroid dehydrogenase activity, by contrast, was not affected by ABT, indicating specificity for P 450-catalyzed reactions. The results demonstrate that ABT in vivo is a non-selective inhibitor of adrenal steroid- and xenobiotic-metabolizing P 450 isozymes. The absence of ABT effects on steroid metametabolism in vitro suggests that an extra-adrenal metabolite may mediate the in vivo inhibition of steroidogenesis.

  • Inactivation of adrenal cytochromes P450 by 1Aminobenzotriazole: Divergence of in vivo and in vitro actions
    Biochemical pharmacology, 1995
    Co-Authors: Howard D. Colby, Brian Abbott, Michael Cachovic, Kristine M. Debolt, Bruce A. Mico

    Abstract Recent investigations demonstrated that administration of 1Aminobenzotriazole (ABT) to rats caused adrenal gland enlargement. Studies were done to pursue the mechanism(s) involved. Preliminary experiments revealed that the adrenal enlargement caused by ABT was associated with a decline in plasma corticosterone concentrations, suggesting inhibition of adrenal steroidogenesis. Indeed, a single injection of ABT (25 or 50 mg/kg body weight) to rats caused concentration-dependent declines (60–80%) in adrenal mitochondrial and microsomal cytochrome P450 (P450) concentrations. The decreases in adrenal P450 levels exceeded those in hepatic microsomes. Accompanying the declines in adrenal P450 concentrations were decreases in steroid hydroxylase activities. Mitochondrial 11β-hydroxylase and cholesterol side-chain cleavage activities and microsomal 21-hydroxylase activity were diminished markedly (60–90%) by ABT treatment. In contrast, activity of adrenal 3β-hydroxysteroid dehydrogenase-isomerase was not affected by ABT, indicating specificity for P450-dependent reactions. Incubation of adrenal microsomes or mitochondria in vitro with ABT plus an NADPH-generating system had no effect on P450 concentrations or on steroid hydroxylase activities. Similar incubations with hepatic microsomes caused declines in P450 levels and in the rates of P450-mediated xenobiotic metabolism. The results demonstrate that ABT is a potent inhibitor of adrenal steroid hydroxylases in vivo , but the in vitro studies indicate that the mechanism of action differs from that on other P450 isozymes. The absence of inhibitor effects in vitro suggests that an extra-adrenal metabolite of ABT is responsible for the in vivo inactivation of steroidogenic enzymes.

John R. Bend – One of the best experts on this subject based on the ideXlab platform.

  • Potentiation of oxygen-induced lung injury in rats by the mechanism-based cytochrome P-450 inhibitor, 1Aminobenzotriazole.
    The Journal of pharmacology and experimental therapeutics, 2000
    Co-Authors: Bhagavatula Moorthy, John R. Bend, Charles V. Smith, Kristen M Parker, Stephen E. Welty

    In this investigation, we tested the hypothesis that the cytochrome P-450 (CYP) inhibitor 1Aminobenzotriazole (ABT) alters the susceptibility of rats to hyperoxic lung injury. Male Sprague-Dawley rats were treated i.p. with ABT (66 mg/kg), i.v. with N -benzyl-1Aminobenzotriazole (1 μmol/kg), or the respective vehicles, followed by exposure to >95% oxygen for 24, 48, or 60 h. Pleural effueffusion volumes were measured as estimates of hyperoxic lung injury, and lung microsomal ethoxyresorufin O -deethylation (EROD) (CYP1A1) activities and CYP1A1 apoprotein levels were determined by Western blotting. ABT-pretreated animals exposed to hyperoxia died between 48 and 60 h, whereas no deaths were observed with up to 60 h of hyperoxia in vehicle-treated animals. In addition, three of four ABT-treated rats exposed to hyperoxia for 48 h showed marked pleural effusions. Exposure of vehicle-treated rats to hyperoxia led to 6.3-fold greater lung EROD activities and greater CYP1A1 apoprotein levels than in air-breathing controls after 48 h, but both declined to control levels by 60 h. Liver CYP1A1/1A2 enzymes displayed responses to hyperoxia and ABT similar to the effects on lung CYP1A1. N -Benzyl-1Aminobenzotriazole markedly inhibited lung microsomal pentoxyresorufin O -depentylation (principally CYP2B1) activities in air-breathing and hyperoxic animals but did not affect lung EROD or liver CYP activities. In conclusion, the results suggest that induction of CYP1A enzymes may serve as an adaptive response to hyperoxia, and that CYP2B1, the major pulmonary CYP isoform, does not contribute significantly to hyperoxic lung injury.

  • Enantioselective, Mechanism-Based Inactivation of Guinea Pig Hepatic Cytochrome P450 byN-(α-Methylbenzyl)-1Aminobenzotriazole
    Drug metabolism and disposition: the biological fate of chemicals, 1998
    Co-Authors: Christopher J. Sinal, Maurice Hirst, Christopher D. Webb, John R. Bend

    N -Aralkylated derivatives of 1Aminobenzotriazole are well-established, mechanism-based inhibitors of cytochrome P450 (CYP or P450). In this study, the kinetics of inactivation of CYP2B-dependent 7-pentoxyresorufin O -depentylation (PROD) and CYP1A-dependent 7-ethoxyresorufin O -deethylation (EROD) activities by enantiomers of N -(α-methylbenzyl)-1Aminobenzotriazole (αMB) were compared. The racemic mixture (±)-αMB, as well as the enantiomers (−)-αMB and (+)-αMB, produced a time-, concentration-, and NADPH-dependent loss of PROD and EROD activity in hepatic microsomes from phenobarbital-treated guinea pigs. The rates of PROD inactivation by (−)-αMB were significantly faster than for (+)-αMB. Consistent with this, the derived maximal k inact was also significantly greater for (−)-αMB than for (+)-αMB (0.49 vs. 0.35 min −1 ). In contrast, the concentrations required for the half-maximal rate of inactivation ( K i ) were equivalent for (−)-αMB and (+)-αMB, whereas the degree of competitive inhibition of PROD activity was greater for (+)-αMB. No significant differences were found among (−)-αMB, (+)-αMB, and (±)-αMB with respect to mechanism-based inactivation ( k inact = 0.18, 0.16, and 0.17 min −1 , respectively) or competitive inhibition of EROD activity. No differences were found for the maximal extent of PROD or EROD inhibition or the loss of spectral P450 after an extended 30-min incubation with the inhibitors. We conclude that mechanism-based inactivation of guinea pig CYP2B, but not CYP1A, isozymes by αMB occurs in a stereoselective manner, most likely as a result of a difference in the balance between metabolic activation and deactivation for the αMB enantiomers.

  • Significance of Glycine 478 in the Metabolism of N-Benzyl-1Aminobenzotriazole to Reactive Intermediates by Cytochrome P450 2B1
    Biochemistry, 1997
    Co-Authors: Ute M. Kent, John R. Bend, Imad H. Hanna, Grazyna D. Szklarz, Alfin D. N. Vaz, James R. Halpert, Paul F. Hollenberg

    The effect of mutating Gly 478 to Ala in rat cytochrome P450 2B1 on the metabolism of N-benzyl-1Aminobenzotriazole was investigated. The 7-ethoxy-4-(trifluoromethyl)coumarin O-deethylation activity of the wild-type enzyme was completely inactivated by incubating with 1 microM BBT. The G478A mutant, however, was not inactivated by incubating with up to 10 microM BBT. Whereas metabolism of BBT by the wild-type 2B1 resulted in the formation of benzaldehyde, benzotriazole, Aminobenzotriazole, and a new metabolite, the G478A mutant generated only the later. This metabolite was found by NMR, IR, and mass spectrometry to be a dimeric product formed from the reaction of two BBT molecules. Two spectral binding constants, a high-affinity constant that was the same for both enzymes (30-39 microM) and a low-affinity constant that was 5-fold lower for the mutant enzyme (0.3 mM vs 1.4 mM), were observed with BBT. The apparent Km and kcat values for the G478A mutant with BBT were 0.3 mM and 12 nmol (nmol of P450)-1 min-1, respectively. Molecular modeling studies of BBT bound in the active site of P450 2B1 suggested that a mutation of Gly 478 to Ala would result in steric hindrance and suppress oxidation of BBT at the 1-amino nitrogen. When BBT was oriented in the 2B1 active site such that oxidation at the 7-benzyl carbon could occur, no steric overlap between Ala 478 and the substrate was observed. Thus, this orientation of BBT would be preferred by the mutant leading to oxidation at the 7-benzyl carbon and subsequent dimer formation. These findings indicate that a glycine 478 to alanine substitution in P450 2B1 altered the binding of BBT such that inactivating BBT metabolites were no longer generated.