Abstract 770: Gender differences in the expression of drug metabolizing enzymes in human liver tissues

Abstract

Abstract Differences in pharmacokinetics and drug metabolism present a major challenge in treatment of diseases, such as cancer, as they contribute to variations that characterizes how well drugs respond. Variation in the expression of major drug metabolizing enzymes (DMEs) is associated with significant differences in the bioavailability, distribution, metabolism and clearance of drugs and other xenobiotics. Previous mice/rats studies have shown genetic variation, or polymorphism, in these DMEs is one of the most important causes of variable drug response. It is essential not just in terms of how they affects drug efficacy but in how drugs affect the enzymes. A particular drug may inhibit the metabolic activity of certain DMEs which may lead to deadly levels of drug concentration and an increase in the severity of adverse side effects. On the contrary, when enzymatic activity is induced, drug concentration may decrease, severely limiting its performance. Given the important role of DMEs in regulating the pharmacological and biological activity of drugs it is essential to understand the regulatory features that lead to individual differences in the DMEs expression. Several factors contribute to individual differences in DME expression and drug metabolism. One of which is the differences contributed due the sex/gender of the subjects. In order to understand how sex differences in human may differ in terms of expression in DME, we compared gene expression in male and female human liver tissues, the liver being an important drug metabolizing tissue. Microarray analysis and real time PCR were utilized to identify significant changes in DME expression in hepatic tissues. Microarray analysis identified 34 sex-differential metabolizing enzymes in normal human livers at the RNA level. Of these, we focused on the expression of five metabolizing enzymes: CYP2B6, CYP1A1, CYP11A1, UGT2B15, GST-alpha. These five genes play potential roles in how anti-cancer drugs are metabolized and eliminated from the liver. mRNA expression for these five metabolizing enzymes were significantly higher in normal male human livers compared to female. At the protein levels, significant differences were only shown in CYP2B6 (p<0.05), CYP1A1 (p<0.01) and UGT2B15 (p<0.05). CYP2B6, CYP1A1 and UGT2B15 protein expressions were significantly higher in male compared to age-matched female. There were no significant changes in the protein expression of CYP11A1 AND GST-alpha between age-matched male and female human liver tissues. These studies show gender differences in liver DME expression and provide further insights into how the expression of hepatic enzymes active in the metabolism of drugs may contribute to gender differences at the clinic level in drug efficacy and toxicity, especially with anticancer agents. Citation Format: Stancy J. Joseph, Tamara Nicolson, Honggang Wang, Beverly R. Word, George Hammons, Beverly Lyn-Cook. Gender differences in the expression of drug metabolizing enzymes in human liver tissues. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 770. doi:10.1158/1538-7445.AM2014-770