Imaoka S, Sugiyama T, Taniguchi N, Funae Y
Laboratory of Chemistry, Osaka City University Medical School, Japan.
Carcinogenesis. 1993 Jan;14(1):117-21. doi: 10.1093/carcin/14.1.117.
The expression of 14 forms of cytochrome P450 in the liver as well as changes in the testosterone hydroxylation activities of hepatic microsomes were investigated during the development of hepatitis in Long-Evans Cinnamon (LEC) rats. P4501A1 and -1A2 (3-methylcholanthrene-inducible forms) and P4502B1 and -2B2 (phenobarbital-inducible forms) were barely detected in the hepatic microsomes of male and female LEC rats. In immature male rats, the levels of male-specific forms (P4502C11 and -2C13) were higher in LEC rats than in control Long-Evans Agouti (LEA) rats. P4502C11 appeared in female LEC rats from 4 to 16 weeks of age, reflecting that testosterone 2 alpha- and 16 alpha-hydroxylation activities were detected at significant levels in female LEC rats. In immature female rats, the level of P4502C12 (a major female-specific form) was higher in LEC rats than in LEA rats. The level of P4502C13 in male LEC rats and that of P4502C12 in female LEC rats decreased markedly with ageing or during the development of hepatitis. The level of P4503A2 (a male-predominant form) was especially high in immature male and female LEC rats, reflecting that both rats had high 2 beta- and 6 beta-hydroxylation activities toward testosterone. These sex-specific forms are regulated by androgens and by pituitary growth hormone. Thus, there may be abnormalities of the hypothalamo-pituitary-gonadal axis in LEC rats. Furthermore, P4503A2 efficiently activates aflatoxin B1, a potent hepatocarcinogen, and the increased levels of this form in LEC rats may be related to the onset of hepatitis or liver cancer.
在长 Evans 肉桂色（LEC）大鼠肝炎发展过程中，研究了肝脏中 14 种细胞色素 P450 的表达以及肝微粒体睾酮羟化活性的变化。雄性和雌性 LEC 大鼠的肝微粒体中几乎检测不到 P4501A1 和 -1A2（3 - 甲基胆蒽诱导型）以及 P4502B1 和 -2B2（苯巴比妥诱导型）。在未成熟雄性大鼠中，LEC 大鼠雄性特异性形式（P4502C11 和 -2C13）的水平高于对照长 Evans 刺鼠（LEA）大鼠。P4502C11 在 4 至 16 周龄的雌性 LEC 大鼠中出现，这反映出在雌性 LEC 大鼠中检测到显著水平的睾酮 2α - 和 16α - 羟化活性。在未成熟雌性大鼠中，LEC 大鼠的 P4502C12（一种主要的雌性特异性形式）水平高于 LEA 大鼠。雄性 LEC 大鼠的 P4502C13 水平和雌性 LEC 大鼠的 P4502C12 水平随着年龄增长或肝炎发展而显著下降。P4503A2（一种雄性占主导的形式）在未成熟雄性和雌性 LEC 大鼠中水平特别高，这反映出两种大鼠对睾酮都有较高的 2β - 和 6β - 羟化活性。这些性别特异性形式受雄激素和垂体生长激素调节。因此，LEC 大鼠可能存在下丘脑 - 垂体 - 性腺轴异常。此外，P4503A2 能有效激活强效肝致癌物黄曲霉毒素 B1，LEC 大鼠中这种形式水平的升高可能与肝炎或肝癌的发生有关。
