N4-hydroxylation of sulfamethoxazole by cytochrome ...
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| Title | N4-hydroxylation of sulfamethoxazole by cytochrome P450 of the cytochrome P4502C subfamily and reduction of sulfamethoxazole hydroxylamine in human and rat hepatic microsomes |
| Author(s) | A. Cribb, S. Spielberg, G. Griffin |
| Journal | Drug metabolism and disposition: the biological fate of chemicals |
| Date | 1995 |
| Volume | 23 |
| Issue | 3 |
| Start page | 406 |
| End page | 414 |
| Abstract | The N4-hydroxylation of sulfamethoxazole (SMX) to its hydroxylamine (SMX-HA) metabolite is the first step in the formation of reactive metabolites responsible for mediating hypersensitivity reactions associated with this compound. In rat hepatic microsomes, the NADPH-dependent oxidation of SMX to SMX-HA was increased 3-fold by pretreatment of rats with phenobarbital. Other cytochrome P450 (CYP) inducers were ineffective. The constitutive and induced SMX N-hydroxylation activities were inhibited by tolbutamide, and induction of SMX-HA activity paralleled the induction of progesterone 21-hydroxylase activity, a marker for CYP2C6. SMX N-hydroxylation in phenobarbital-treated rat hepatic microsomes was inhibited 70% by anti-CYP2C6 antisera. Thus, the N4-hydroxylation of SMX by rat hepatic microsomes was mediated by members of the CYP2C subfamily, probably CYP2C6. In a panel of human microsomes, SMX-HA formation correlated with tolbutamide hydroxylase activity (r = 0.75; p = 0.01); CYP2C9 content (r = 0.79; p or = 1 microM inhibited the reduction of SMX-HA in human hepatic microsomes by 45%, whereas sulfaphenazole had no effect.(ABSTRACT TRUNCATED AT 250 WORDS) |
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