At least six forms of extremely homologous cytochromes P-450 in rat liver are encoded at two closely linked genetic loci.

A subpopulation of phenobarbital-induced cytochrome P-450 in rat liver has been shown to consist of four closely related forms of the enzyme that appeared to be strain-related. In the present study, polypeptides composing this family were analyzed by two-dimensional electrophoresis of hepatic microsomes from 64 individual phenobarbital-treated rats. The animals surveyed included both sexes from four inbred and five outbred strains/colonies and F1 progenies from 10 crosses. Two new members of this polypeptide family were identified on the basis of their unique electrophoretic behavior and peptide maps. Eight phenotypes were observed that consisted of two to four member polypeptides. The six closely related cytochromes P-450 were found to be encoded at two genetic loci with at least four alleles at the P-450b locus and at least two alleles at the P-450e locus. Most colonies of outbred strains were characterized by polymorphism at one or both of these loci, and in no case did they contain unique alleles. Analyses of parents and their F1 progenies indicated that the P-450b and P-450e loci are closely linked on the same autosome and are expressed codominantly. Furthermore, the products of these loci appear to be coordinately regulated. The extreme homology between P-450b and P-450e genes, their high degree of polymorphism, and their close linkage suggest that they are subject to the same genetic mechanisms that maintain these features in other multigene families.