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.
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.
K
K
Sugihara
S
S
Kitamura
S
S
Sanoh
S
S
Ohta
N
N
Fujimoto
S
S
Maruyama
A
A
Ito
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