Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone (original) (raw)
2001, British Journal of Clinical Pharmacology
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Both cytochromes P450 2E1 and 1A1 are involved in the metabolism of chlorzoxazone
Chemical Research in Toxicology, 1993
Chlorzoxazone, a centrally acting muscle relaxant, was previously shown to be hydroxylated on carbon 6 specifically by cytochrome P450 2E1. Accordingly, this drug has been proposed as a potential noninvasive in-vivo probe for screening the hepatic P450 2E1 activity. This study was carried out to test the specificity of such a substrate when first experiments conducted by using human hepatocyte cultures showed that the chlorzoxazone 6-hydroxylation activity increased after 3-methylcholanthrene treatment of cells. Indeed, the ability of both rat and human hepatocytes to metabolize chlorzoxazone significantly increased after treatments by 3-methylcholanthrene alone or plus ethanol, suggesting the involvement of P450 1A enzymes in this oxidative reaction. Identical results were obtained by in-vivo treatment of rats with four inducers of P450 1A enzymes, namely, 0-naphthoflavone, isosafrole, Arochlor 1254, and 3-methylcholanthrene. Furthermore, the chlorzoxazone 6-hydroxylation activity was inhibited by both a-naphthoflavone and dimethyl sulfoxide, both known to inhibit P450 1A and P450 2E1 activities, respectively. Finally, the use of yeasts genetically engineered for expression of human P450 1AlI1A2, 2C9, and 3A4 demonstrated that P450 1Al was significantly involved in this catalytic activity. In conclusion, these results taken together suggest that chlorzoxazone should be used with precaution as in-vivo tool for evaluating P450 2E1. However, the relative K, of P450 1Al and 2E1 for chlorzoxazone and, on the other hand, the relative levels of these two enzymes in the human liver suggest that P450 2E1 would generally be the major form metabolizing chlorzoxazone in-vivo. 0 Abstract published in Aduance ACS Abstracts, October 1, 1993.
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