Intraspecies individuality for the metabolism of steroids

1. A variety of regulatory factors contribute to differences in the rates of 6β-hydroxylation, 16α-hydroxylation and 21-hydroxylation of progesterone as catalysed by liver microsomes prepared from individual rabbits.

2. It is likely that the 6β-hydroxylation of progesterone is catalysed primarily by cytochrome P-450 3c, an enzyme that exhibits allosteric activation by α-napthoflavone, and by a form of P-450 3b, 6β⁺, that is expressed in some rabbits in an autosomal dominant manner.

3. 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.

4. A second form of P-450 3b, 6β^-, catalyses a major portion of hepatic progesterone 16α-hydroxylation and exhibits activation by a variety of C21 steroids of which 5β-pregnane-3β,20α-diol is the most efficacious.

5. 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.

6. 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.

7. The P-450 1-related gene product is expressed in liver to a similar degree in both 21H and 21L rabbits.