Cytochrome P450 1A1/2 Mediated Metabolism of trans-Stilbene in Rats and Humans

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It was demonstrated that trans-stilbene was metabolically activated to the estrogenic compound by rat liver microsomes (Sugihara et al., Toxicol. Appl. Pharmacol., 167,46-54 (2000)). In this study, determination of the isoforms of cytochrome P450 involved in the oxidation of the proestrogen, trans-stilbene, to its hydroxylated metabolites was examined. When trans-stilbene was incubated with rat liver microsomes in the presence of NADPH, estrogenic compounds, trans-4-hydroxystilbene and trans-4,4'-dihydroxystilbene were formed. Comparison of the oxidase activity among liver microsomes of untreated, 3-methylcholanthrene-treated, acetone-treated, clofibrate-treated, dexamethasone-treated and phenobarbital-treated rats toward trans-stilbene showed that those from 3-methylcholanthrene-treated rats exhibited the highest activity. Human liver microsomes also catalyzed the oxidation in varying degrees. Variation in trans-stilbene oxidase activity was closely correlated to that of phenacetin O-deethylase activity. The oxidase activity was inhibited by α-naphthoflavone ; however, in this case trans-4,4'-dihydroxystilbene was not detected. The oxidase activity toward trans-stilbene was exhibited by recombinant human cytochrome P450 1A1 and 1A2 expressed in a human B lymphoblastoid cell line.
公益社団法人日本薬学会の論文
2002-03-01