Intraspecies individuality for the metabolism of steroids

A variety of regulatory factors contribute to differences in the rates of 6 beta-hydroxylation, 16 alpha-hydroxylation and 21-hydroxylation of progesterone as catalysed by liver microsomes prepared from individual rabbits. It is likely that the 6 beta-hydroxylation of progesterone is catalysed primarily by cytochrome P-450 3c, an enzyme that exhibits allosteric activation by alpha-napthoflavone, and by a form of P-450 3b, 6 beta+, that is expressed in some rabbits in an autosomal dominant manner. The mechanism of activation for P-450 3c appears to reflect an effector mediated increase of the affinity of the enzyme for substrate as judged by substrate binding studies. A second form of P-450 3b, 6 beta-, catalyses a major portion of hepatic progesterone 16 alpha-hydroxylation and exhibits activation by a variety of C21 steroids of which 5 beta-pregnane-3 beta,20 alpha-diol is the most efficacious. P-450 1, which catalyses the 21-hydroxylation of progesterone, is expressed at 10-fold higher levels in the 21H phenotype than the 21L phenotype, and the former is inherited as an autosomal dominant characteristic. A cDNA encoding a P-450 1-related gene product exhibits a predicted amino acid sequence that is 95% homologous to that of P-450 1. The P-450 1-related gene product is expressed in liver to a similar degree in both 21H and 21L rabbits.