Tissue-specific regulation of cytochrome P-450 dependent testosterone 15α-hydroxylase

Abstract

Testosterone 15α-hydroxylase activity in kidney microsomes is higher in male mice than in female mice, while in the liver the activity is higher in females than in males. Cytochrome P-45Q15α, a specific form of cytochrome P-450 having testosterone 15α-hydroxylase activity, accounts for virtually all of the testosterone 15α-hydroxylase activity in female kidney microsomes, while other isozymes of testosterone 15α-hydroxylase are present in male kidney microsomes. In female kidney, P-45015α expression is regulated by a single sex-dependent locus, called Rsh for "regulation of steroid hydroxylase." The higher level of P-45015α expression in male kidneys is dependent on androgens. Of all mice strains, 129/J seems to be the least dependent on androgens to maintain a high expression of P-45015α in male kidneys. Castration of male mice lowers kidney levels of P-45015α but in the liver, P-45015α, levels rise after castration. This reciprocal regulation of P-45015α genes in liver and kidney was investigated by isolating cDNA clones encoding P-45015α from liver and kidney cDNA libraries. Two highly homologous cDNA clones encoding P-45015α designated type I and type II were identified, and levels of type I and type ÏI mRNA in liver and kidney were determined by differential restriction mapping of double-stranded cDNA prepared from mRNA from these tissues. Only type I mRNA is present in male kidney and only type II mRNA is present in female kidney, while both type I and type II mRNA are present in liver. Castration results in decreased levels of type I mRNA in male kidney but increased levels of type I mRNA in male liver. The levels of type II mRNA are not affected by androgens. We conclude that type I gene is induced in male kidneys and repressed in male liver by androgens, while type II gene expression is not affected by androgens.Key words: cytochrome P-450, 15α-hydroxylase, androgen-dependent expression, tissue-specific expression.