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. Studies were done to evaluate the effects of age and gender on adrenal CYP2D16 expression and xenobiotic metabolism. In both male and female guinea pigs at 1, 7, 14, or 30 weeks of age, in situ hybridization and immunohistochemistry 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 not age- or gender-dependent. However, the proportion of each adrenal gland comprised by ZR and thus expressing CYP2D16 increased with aging in both sexes and was greater in males than in females. The rates of metabolism of bufuralol, a CYP2D-selective substrate, by adrenal microsomal preparations generally correlated with the amount of ZR (and CYP2D16) in the gland. Thus, adrenal xenobiotic-metabolizing activities were greater in males than in females at all ages and increased with aging in males. However, the rates of bufuralol 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 estrogens on enzyme activity. The results indicate that the age and gender differences in adrenal CYP2D16 content are largely determined by differences in the size of the ZR rather than the concentrations of CYP2D16 within cells of the ZR. However, adrenal xenobiotic-metabolizing activities in females seem to be further modulated by an inhibitory effect of estrogens.
Yuan
B B
BB
Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy and Science, Philadelphia, Pennsylvania, USA.
Tchao
R
R
Voigt
J M
JM
Colby
H D
HD
D015660:7-Alkoxycoumarin O-Dealkylase / Q000378:metabolism; D000302:Adrenal Cortex / Q000201:enzymology* / Q000254:growth & development / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D015151:Immunoblotting; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D012737:Sex Factors; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism; D015262:Xenobiotics / Q000378:metabolism*; D015383:Zona Fasciculata / Q000201:enzymology / Q000254:growth & development / Q000378:metabolism; D015385:Zona Reticularis / Q000201:enzymology / Q000254:growth & development / Q000378:metabolism
D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D001189:Aryl Hydrocarbon Hydroxylases; C118568:cytochrome P-450 CYP2D16 (guinea pig); D013254:Steroid 17-alpha-Hydroxylase; C043872:bufuralol 1'-hydroxylase