Gorski J R, Arlotto M P, Klaassen C D, Parkinson A
Carcinogenesis. 1985 Apr;6(4):617-24. doi: 10.1093/carcin/6.4.617.
The present studies were undertaken to resolve conflicting reports on the inducibility of liver microsomal benzo[a]pyrene hydroxylase activity in rats treated with pregnenolone-16 alpha-carbonitrile (PCN). Several studies have shown that treatment of Long Evans rats with PCN causes a 5- to 10-fold induction of benzo[a]pyrene hydroxylase activity, whereas little or no induction occurs in Sprague-Dawley or Wistar rats. Studies with one-month-old-male Long Evans, Sprague-Dawley, Wistar and Holtzman rats failed to reveal an anticipated strain difference in the inducibility of benzo[a]pyrene hydroxylase activity by PCN. Studies with immature and mature male and female Long Evans rats revealed that the inducibility of benzo[a]pyrene hydroxylase activity decreases with age in male but not female rats, i.e., PCN induced benzo[a]Pyrene hydroxylase activity 5- to 8-fold in immature male, immature female and mature female rats but only 2-fold in mature male rats. The age-dependent decrease in inducibility by PCN in male rats coincided with an age-dependent increase (2.4-fold) in the basal activity of benzo[a]pyrene hydroxylase. These sex-dependent developmental changes can be explained by an age-dependent increase in the constitutive levels of the major PCN-inducible form of cytochrome P-450 (cytochrome P-450-PCN) in male but not female rats. Electrophoresis of liver microsomes and studies on the binding of metyrapone to dithionite-reduced cytochrome P-450 provided additional evidence for age- and sex-dependent differences in the levels of microsomal cytochrome P-450-PCN. In addition to reconciling the conflicting literature reports, the age- and sex-dependent differences in cytochrome P-450-PCN levels account, at least in part, for age and sex differences in certain liver microsomal enzyme activities, including benzo[a]pyrene hydroxylase activity.
本研究旨在解决关于孕烯醇酮 - 16α - 腈（PCN）处理的大鼠肝脏微粒体苯并[a]芘羟化酶活性诱导性的相互矛盾的报道。多项研究表明，用PCN处理长 Evans 大鼠会导致苯并[a]芘羟化酶活性诱导 5至10倍，而在斯普拉格 - 道利或Wistar大鼠中几乎没有诱导作用。对1月龄雄性长 Evans、斯普拉格 - 道利、Wistar和霍尔茨曼大鼠的研究未能揭示PCN对苯并[a]芘羟化酶活性诱导性方面预期的品系差异。对未成熟和成熟的雄性及雌性长 Evans 大鼠的研究表明，苯并[a]芘羟化酶活性的诱导性在雄性大鼠中随年龄降低，而在雌性大鼠中并非如此，即PCN在未成熟雄性、未成熟雌性和成熟雌性大鼠中诱导苯并[a]芘羟化酶活性5至8倍，但在成熟雄性大鼠中仅诱导2倍。雄性大鼠中PCN诱导性随年龄的降低与苯并[a]芘羟化酶基础活性随年龄的增加（2.4倍）相吻合。这些性别依赖性的发育变化可以通过雄性大鼠而非雌性大鼠中细胞色素P - 450主要PCN诱导形式（细胞色素P - 450 - PCN）组成水平随年龄的增加来解释。肝脏微粒体的电泳以及美替拉酮与连二亚硫酸盐还原的细胞色素P - 450结合的研究为微粒体细胞色素P - 450 - PCN水平的年龄和性别依赖性差异提供了额外证据。除了调和相互矛盾的文献报道外，细胞色素P - 450 - PCN水平的年龄和性别依赖性差异至少部分解释了某些肝脏微粒体酶活性的年龄和性别差异，包括苯并[a]芘羟化酶活性。
