Age- and sex-related alterations of microsomal drug- and testosterone- oxidizing cytochrome P450 in Sprague-Dawley strain-derived dwarf rats

Effect of growth hormone (GH) on the age-related changes in hepatic cytochrome P450 (P450) was studied using GH-deficient dwarf and parental Sprague-Dawley rats. Microsomal testosterone (T) T2α- and T2β- hydroxylations were lower in livers of mature male dwarf rats than the normals, whereas T16β-hydroxylation was rather higher in male dwarf rats. Although T2α-, T2β-, T6β-, T16α- and T16β-hydroxylations were barely detectable in senescence normal rats (24 months old), considerable levels of T6β-, T16α- and T16β-hydroxylations were maintained in senescence dwarf rats (after 22 months old). These results are caused by the alteration of specific P450 forms including CYP2B1, CYP2B2, CYP2C11 and CYP3A2 in dwarf rats. Appearance of male-specific CYP2C11 and CYP3A2 and high levels of CYP2B1 and CYP2B2 in female dwarf rats indicate the role of pituitary GH on liver of normal rats. However, the additional role of a factor other than GH was suggested on the sex-related differences and age-associated alterations of specific P450 contents in dwarf rats. CYP2C11 appears in dwarf female rats with the same developmental profile as observed in normal male rats. This form appears apparently with the development of GH receptor in livers, suggesting the possibility that a factor independent from androgen and GH governs the ontogeny of this P450 in the liver. A female-specific protein, CYP2C12, in normal rat livers, also appeared in both sexes of senescence dwarf rats, suggesting the role of non-GH factor on the expression of this P450 in liver.