Inactivation of adrenal cytochromes P450 by 1-aminobenzotriazole: Divergence of in vivo and in vitro actions
Recent investigations demonstrated that administration of 1-aminobenzotriazole (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 co...
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Veröffentlicht in: | Biochemical pharmacology 1995-04, Vol.49 (8), p.1057-1062 |
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Sprache: | eng |
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Zusammenfassung: | Recent investigations demonstrated that administration of 1-aminobenzotriazole (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. |
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ISSN: | 0006-2952 1873-2968 |
DOI: | 10.1016/0006-2952(95)98501-Y |