Gender-specific patterns of testosterone secretion contribute to the expression of cytochrome P450 3A1 and 3A2

• Main Authors: Hui-ChinChen, 陳慧瑾
• Other Authors: Jin-Ding Huang
• Format: Others
• Language: zh-TW
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/47205706141967643058

碩士 === 國立成功大學 === 藥理學研究所 === 100 === Cytochrome P450 monooxygenases (CYPs) is a superfamily of hemoproteins responsible for the biotransformation of many exogenous and endogenous chemicals. Our laboratory previously reported that the influence of CYP3A5 expression on the pharmacokinetics is associated with gender and the location of small intestine. However the mechanisms involved in this physiological regulation have not yet been characterized. Human expresses two major cytochrome P450 isoforms, CYP3A4 and CYP3A5 that are oligomerically related to rats CYP3A1 and CYP3A2. In order to clarify whether the gender-related differences in the hepatic and intestinal expression of CYP3As are present, we have characterized expression of CYP3A1 protein and CYP3A2 protein in hepatocytes and small intestinal enterocytes of rat. The preliminary results showed age-associated decline in liver CYP3A1 expression in both sexs, whereas it increased in intestine. CYP3A1 is much higher in the liver than in the duodenum, jejunum and ileum. CYP3A2 was expressed in liver in 10-day in both sexs. However, the levels decreased over time and disappeared in female at 10 weeks of age. CYP3A2 was undetectable in intestine in either male or female at any age. Male rats expressed more CYP3As protein than females. Recent studies have implicated hormone regulates sex-dependent CYP450s through the interaction of the hormone-receptor complex with gene cis-acting elements. To further investigate the effect of testosterone on the expression of CYP3As, we used androgen ablation therapy by chemical or surgical castration. Androgen ablation therapy led to significantly reduction in the CYP3A1 and CYP3A2 in liver. The alternations can be reversed by testosterone replacement. Taken together, these results suggest complex gender-, tissue- and development-specific patterns which are controlled by hormones of the CYP 3As expression. Key word: testosterone; CYP3A1; CYP3A2