Role of mouse CYP2A5 in nicotine clearance and testosterone homeostasis

Abstract

CYP2A5, a mouse P450 enzyme, is expressed abundantly in the olfactory mucosa (OM), and in other tissues, including the liver and the lateral nasal gland (LNG). To determine the biological and pharmacological functions of CYP2A5 in vivo, we have generated a Cyp2a5‐null mouse. Homozygous Cyp2a5‐null mice are viable and fertile. OM microsomes from Cyp2a5‐null mice had significantly lower activities in the metabolism of testosterone (T) than did OM microsomes from wild‐type (WT) mice. In contrast, hepatic microsomes from Cyp2a5‐null mice showed only small decreases in the overall rates of formation of T metabolites, compared to hepatic microsomes from WT mice. Serum T levels were not altered by the loss of CYP2A5 function in male mice, a result confirming that CYP2A5 does not play a major role in systemic T clearance in vivo. Nevertheless, loss of CYP2A5 was accompanied by significant increases in tissue levels of T in the LNG, a gland important for nasal mucus secretion and production of odorant binding proteins. The Cyp2a5‐null mice also showed decreased clearance of nicotine, with significant increases in the half life and AUC values for serum nicotine, compared with WT mice. These findings indicate that CYP2A5 is the major nicotine oxidase in the mouse liver, and that CYP2A5 plays an important role in the regulation of T levels in the LNG of male mice. (Supported in part by NIH grant ES‐07462)