Ovarian Metabolism of Xenobiotics

Abstract

Chemicals that cause loss of ovarian follicles are of toxicological importance because females are born with a finite number of primordial follicles. Premature loss of this follicle pool can accelerate the time to ovarian senescence or menopause in women, ultimately reducing the reproductive life span. Many, but by no means all, xenobiotics require metabolism or biotransformation to a chemically reactive intermediate to induce toxicity. This is also true for most ovarian toxicants. Even though the liver is the primary organ involved in the metabolism or biotransformation of xenobiotics, extrahepatic organs such as the ovary have the capacity to participate in metabolism. This extrahepatic metabolism, especially bioactivation, can pose a problem if the organ metabolizing xenobiotics to their reactive intermediates is also the target organ because target organ metabolism of xenobiotics could potentiate toxicity induced by hepatic metabolism. The ovary expresses enzymes involved in phase I and II metabolism, and it is capable of metabolizing xenobiotics. For example, ovarian toxicants 4-vinylcyclohexene monoepoxide (VCM) and 7,12-dimethylbenz[a]anthracene (DMBA) require bioactivation to induce follicle loss. VCM-induced ovarian toxicity requires the ovarian cytochrome P450 (CYP P450) 2E1 enzyme in the absence of hepatic bioactivation. However, studies indicate that in the presence of hepatic metabolism the ovary plays a minimal role in VCM-induced toxicity. Furthermore, studies have shown that once VCM is bioactivated to the ovotoxic 4-vinylcyclohexene diepoxide (VCD), the ovotoxic metabolite formed can be detoxified by microsomal epoxide hydrolase (mEH) or glutathione conjugation in the ovary. DMBA is sequentially bioactivated to the ovotoxicant DMBA-3,4-diol-1,2-epoxide by CYP 1B1, mEH, and CYP 1A1/1B1 enzymes. Follicle loss induced by the ovotoxicant DMBA in the absence of hepatic tissue was found to involve ovarian mEH enzyme. Additionally, expression of some phase I and II metabolic enzymes is shown to be compartmentalized within the ovary, and expression and activity change as a function of ovarian cycle. As with the liver, the metabolic enzymes in the ovary are also inducible following exposure to xenobiotics, which could result in increased metabolism of these as well as endogenous compounds. The implication of ovarian metabolism of ovotoxicants in the human ovary is not well understood. Human ovary expresses metabolic enzymes and thus has the capacity to participate in the metabolism of ovarian toxicants such as components of cigarette smoke. Collectively, studies have shown that understanding ovarian toxicity induced by protoxicants is a complicated issue including metabolic contributions from not only the liver but also the ovary.