Maturational changes in CYP2D16 expression and xenobiotic metabolism in adrenal glands from male and female guinea pigs

CYP2D16 is expressed at high levels in the zona reticularis (ZR) of guinea pig adrenal glands and contributes to adrenal metabolism of xenobiotics. St udies were done to evaluate the effects of age and gender on adrenal CYP2D1 6 expression and xenobiotic metabolism. In both male and female guinea pigs at 1, 7, 14, or 30 weeks of age, in situ hybridization and immunohistochem istry confirmed that CYP2D16 was highly localized to the ZR of the adrenal gland. The steroidogenic P450 isozyme, CYP17, by contrast, was expressed in both the zona fasciculata and ZR. The intensity of CYP2D16 staining was no t age- or gender-dependent. However, the proportion of each adrenal gland c omprised by ZR and thus expressing CYP2D16 increased with aging in both sex es and was greater in males than in females. The rates of metabolism of buf uralol, a CYP2D-selective substrate, by adrenal microsomal preparations gen erally correlated with the amount of ZR (and CYP2D16) in the gland. Thus, a drenal xenobiotic-metabolizing activities were greater in males than in fem ales at all ages and increased with aging in males. However, the rates of b ufuralol metabolism declined in sexually mature females (14 weeks) from the levels found in prepubertal females (7 weeks) and then increased markedly in retired breeders (30 weeks), suggesting an inhibitory effect of estrogen s on enzyme activity. The results indicate that the age and gender differen ces in adrenal CYP2D16 content are largely determined by differences in the size of the ZR rather than the concentrations of CYP2D16 within cells of t he ZR. However, adrenal xenobiotic-metabolizing activities in females seem to be further modulated by an inhibitory effect of estrogens.