Glucocorticoid and sex hormones as activating or modulating factors for expression of Cyp2b-9 and Cyp2b-10 in the mouse liver and hepatocytes.
The effects of male and female hormones as well as glucocorticoid upon the expression of Cyp2b-9 and Cyp2b-10 were investigated in C57BL/6 mouse liver and hepatocytes in primary culture. Their expression in the untreated female liver was higher than that in the male liver. More Cyp2b-9 mRNA than Cyp2b-10 was present in the female than in the male liver, whereas the levels of Cyp2b-10 were higher in the male. Phenobarbital increased Cyp2b-10 expression more than that of Cyp2b-9 in both sexes. Treatment with beta-estradiol also induced both in the male liver, with more Cyp2b-10 than Cyp2b-9 being found. In the female liver beta-estradiol and testosterone slightly increased the levels of Cyp2b-10, whereas the expression of Cyp2b-9 was reduced. Ovarectomy did not reduce the expression of the two mRNAs, but rather increased them. Using the spheroid culture system, in which mouse hepatocytes were cultured as multicellular aggregates and in which both mRNAs were expressed for a number of days, beta-estradiol as well as phenobarbital potently induced mRNA in hepatocytes from either sex and the inducibility at 10(-5) M corresponded to 10(-3) M phenobarbital. The expression level of Cyp2b-10 mRNA by phenobarbital or beta-estradiol was higher than that of Cyp2b-9, as observed in vivo, and > 10(-7) M beta-estradiol induced both in vitro. Dexamethasone induced the expression of more Cyp2b-10 mRNA than Cyp2b-9, and it was necessary for the expression by either phenobarbital or beta-estradiol. The expression was not enhanced in vitro by concomitant exposure of beta-estradiol and phenobarbital. Among the other female hormones tested, estrone induced Cyp2b-9 and Cyp2b-10 mRNAs at levels equivalent to those induced by beta-estradiol, and estriol and progesterone had a lower potential for the induction. Male hormones, such as androstenedione and testosterone, also had inducing potency in vitro. However, testosterone concentration dependently reduced the expression in cells cultured without dexamethasone. Tamoxifen or cryproterone, having antiestrogenic or antiandrogenic effects, respectively, also induced Cyp2b-9 and Cyp2b-10 mRNA. The suppressive effect of growth hormone on the expression of the mRNA was slight. The observation that endogenous hormones altered the expression of Cyp2b-9 and Cyp2b-10 in vivo and in vitro suggested that male and female hormones, as well as glucocorticoid, play activating or modulating roles in the constitutive expression of P450s.(ABSTRACT TRUNCATED AT 250 WORDS)
Nemoto
N
N
Department of Experimental Pathology, Cancer Institute, Tokyo, Japan.
Sakurai
J
J
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D015342:DNA Probes / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D012739:Gonadal Steroid Hormones / Q000494:pharmacology*; D013006:Growth Hormone / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010052:Ovariectomy; D010634:Phenobarbital / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology
D015342:DNA Probes; D012739:Gonadal Steroid Hormones; D012333:RNA, Messenger; D013739:Testosterone; D004958:Estradiol; D003907:Dexamethasone; D013006:Growth Hormone; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital