Cytochrome P450 1A1/2 mediated metabolism of trans-stilbene in rats and humans.
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, trans4-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 alpha-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.
Sanoh
Seigo
S
Institute of Pharmaceutical Science, Hiroshima University School of Medicine, Japan.
Kitamura
Shigeyuki
S
Sugihara
Kazumi
K
Ohta
Shigeru
S
D000818:Animals; D001711:Biotransformation; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D013267:Stilbenes / Q000378:metabolism* / Q000493:pharmacokinetics
D011994:Recombinant Proteins; D013267:Stilbenes; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2