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  • Because sex steroids and growth hormone play an


    Because sex steroids and growth hormone play an important role in the development and maintenance of hepatic CYP450 enzyme expression and ER expression, it is possible that exposure to endocrine active agents during gestation and perinatally could alter expression of these proteins. Therefore, these experiments were aimed at determining whether estrogenic agents of varying potencies could affect hepatic CYP450 enzyme expression and/or testosterone metabolism and ER in male and female rats. The compounds studied were ethinyl estradiol (EE2), a potent estrogen commonly used in birth control pills; genistein, a soy isoflavone with weak estrogenic properties; and p-nonylphenol, a weakly estrogenic alkylphenol used in the production of commonly used surfactants.
    Materials and methods
    Discussion In general, effects on CYP450 enzymes and testosterone hydroxylase activities were more prominent in male rats than in female rats. Previous studies have demonstrated that high doses of potent estrogens administered to pubertal or adult male rats alter the expression of developmentally regulated sex-specific CYP450s (Mode, Gustafsson, Janssen, Eden, & Isaksson, 1982, Pak, Tsim, & Cheng, 1985, Janeczko, Waxman, Le Blanc, Morville, & Adesnik, 1990). These published studies demonstrate that estrogens can feminize hepatic CYP450 expression and activity profiles in male rats. The mechanism for these effects appears to be feminization of the growth hormone secretion profile via action at the hypothalamic–pitutitary axis (Mode, Gustafsson, Janssen, Eden, & Isaksson, 1982, Janeczko, Waxman, Le Blanc, Morville, & Adesnik, 1990). In SB525334 to the studies mentioned above, our studies examined continuous dietary exposure to estrogenic compounds (EE2, nonylphenol and genistein) from early development (gestation day 7) through puberty (PND 50). The exposure conditions used in the present study undoubtedly resulted in lower blood and tissue concentrations of these compounds than previous studies that have examined the effects of nonylphenol (Lee, Chakraborty, Patra, & Struve, 1996, Masuyama, Hiramatsu, Kunitomi, Kudo, & MacDonald, 2000) or EE2 (Reilly, Mason, & Hooper, 1991, Hallstrom et al., 1996) on CYP3A or CYP2C11 activity due to differences in the route and timing of exposure and/or dose. All three of the test agents produced some alterations in the enzymes examined, but the pattern of changes was complex and not readily explained solely by the estrogenic activities of the test agents. The weakest estrogen tested in terms of estrogen receptor binding affinity (Kuiper et al., 1997), nonylphenol, had the most pronounced effect on both testosterone hydroxylase activities and CYP450 expression. The increase in 5α-reductase activity, decrease in CYP2C11 protein and activity, and decrease in CYP3A1/2 protein in male rats caused by nonylphenol exposure is more consistent with a female pattern of testosterone metabolism than with a male pattern (Pak, Tsim, & Cheng, 1985, Sonderfan, Arlotto, Dutto, McMillen, & Parkinson, 1987). Changes of CYP3A protein and activity or mRNA in the opposite direction (increase) following acute administration of nonylphenol to pups (Lee et al., 1996) or adult males (Masuyama et al., 2000) have been previously reported, while similar decreases in hepatic CYP2C11 and CYP3A1/2 protein and activities following ip injection of a closely related alkylphenol, 4-tert-octylphenol, have recently been published (Hanioka et al., 2000). The differing results with nonylphenol may be the result of the differing exposure regimens or, perhaps, differences in the isomer composition of the administered nonylphenol. Like nonylphenol, genistein affected 5α-reductase,CYP3A and CYP2C11. Genistein treatment resulted in a significant decrease in CYP2C11 activity at the 1250 ppm dose that was accompanied by a non-significant decrease in CYP2C11 protein. CYP3A1/2 protein was also decreased at the highest dose of genistein. Although no decrease in the activity normally associated with CYP3A1 (6β-hydroxylase activity) was observed, this might be explained by the fact that CYP1A1 can also catalyze this reaction (Sonderfan et al., 1987). The effects of genistein on 5α-reductase activity differed from those of nonylphenol in that a significant effect was seen in both sexes and the dose response appeared to be non-monotonic, with the greatest increase in activity at the intermediate (250 ppm) dose and a decrease (significant in males only) in activity at the highest (1250 ppm) dose. Apparent non-monotonic effects of genistein were also found for CYP3A expression in this study and have been reported in other studies. For example, lower genistein concentrations (10 nm–1 μm) stimulated growth of MCF-7 cells, while higher concentrations (10–100 μm) inhibited growth (Wang et al., 1996). In the MCF-7 study, the low dose effects appeared to be mediated through the estrogen receptor, whereas the high-dose effects appeared to be independent of the estrogen receptor. It is possible that genistein is either inhibiting or down-regulating 5α-reductase at the high dose. While Evans et al. (1995) have shown that 100 μm genistein inhibits 5α-reductase activity in tissue homogenates, this explanation seems unlikely since genistein and metabolites have been reported to reach higher concentrations in female rat liver than male rat liver (Chang, Churchwell, Delclos, Newbold, & Doerge, 2000, Coldham, & Sauer, 2000) and no inhibition of 5α-reductase activity was observed in female liver microsomes in our studies.