Mouse steroid 15.alpha.-hydroxylase gene family: identification of type II P-45015.alpha. as coumarin 7-hydroxylase

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Abstract
We identified type II P-45015.alpha. as mouse coumarin 7-hydroxylase (P-450coh). Unlike type I P-45015.alpha., the other member within the mouse steroid 15.alpha.-hydroxylase gene family, type II catalyzed little steriod 15.alpha.-hydroxylase activity, yet structurally there were only 11 substitutions between type I and type II P-45015.alpha.s within their 494 amino acid residues (Lindberg et al., 1989), and the N-terminal sequence (21 residues) of P-450coh was identical with that of both P-45015.alpha.s. Induction by pyrazole of coumarin 7-hydroxylase activity correlated well with the increase of type II P-45015.alpha. mRNA in 129/J male and female mice. Pyrazole, on the other hand, was less in males or not effective in females in inducing the 15.alpha.-hydroxylase activity and type I P-45015.alpha. mRNA. Expression of type I and II in COS-1 cells revealed that the latter catalyzed coumarin 7-hydroxylase activity at 10 to .apprx. 14 pmol min-1 (mg of cellular protein)-1. The former, on the other hand, had a higher testosterone 15.alpha.-hydroxylase but little coumarin 7-hydroxylase activity. It was concluded, therefore, that type II P-45015.alpha. is the mouse coumarin 7-hydroxylase. Identification of type II as the P-450 specific to coumarin 7-hydroxylase activity and characterization of its cDNA and gene, therefore, were significant advances toward understanding the basis of genetic regulation of this activity in mice (known as Coh locus).

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