Metabolic activation of the proestrogens trans-stilbene and trans-stilbene oxide by rat liver microsomes.
A liver microsome-mediated activation of the proestrogens trans-stilbene and trans-stilbene oxide was found in this study. trans-Stilbene and trans-stilbene oxide were negative in estrogen reporter assay using estrogen-responsive human breast cancer cell line MCF-7 and growth assay in rat pituitary tumor cell line MtT/E-2. However, these compounds exhibited estrogenic activity after incubation with liver microsomes of 3-methylcholanthrene-treated rats in the presence of NADPH. In contrast, cis-stilbene and cis-stilbene oxide did not show estrogenic activity after such incubation. When trans-stilbene was incubated with the liver microsomes of 3-methylcholanthrene-treated rats in the presence of NADPH, two metabolites were detected by HPLC. They were identified unequivocally as trans-4-hydroxystilbene and trans-4, 4'-dihydroxystilbene by mass and UV spectral comparison with authentic samples. The oxidase activity of the liver microsomes toward trans-stilbene was inhibited by SKF 525-A and alpha -naphthoflavone. Minor activity was observed when liver microsomes of untreated or phenobarbital-treated rats were used instead of those from 3-methylcholanthrene-treated rats. trans-4-Hydroxystilbene and trans-4,4'-dihydroxystilbene exhibited significant estrogenic activities. These results suggest that the estrogenic activities of trans-stilbene and trans-stilbene oxide were due to formation of hydroxylated metabolites.
Sugihara
K
K
Institute of Pharmaceutical Science, Department of Cancer Research, Research Institute for Radiation Biology and Medicine, Hiroshima University School of Medicine, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima, 734-8551, Japan.
Kitamura
S
S
Sanoh
S
S
Ohta
S
S
Fujimoto
N
N
Maruyama
S
S
Ito
A
A
D000818:Animals; D001711:Biotransformation; D004967:Estrogens / Q000633:toxicity; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013267:Stilbenes / Q000493:pharmacokinetics* / Q000633:toxicity; D014407:Tumor Cells, Cultured
D004967:Estrogens; D013267:Stilbenes; C025906:stilbene oxide