A COMPARISON OF CYTOCHROME P-450-DEPENDENT TESTOSTERONE 2-ALPHA-HYDROXYLASE IN RAT (P-450 2C11) AND MOUSE (P-4502-ALPHA)

Hepatic P-450 2C11 in the rat and P-4502 alpha in the mouse are unique in being the only isoforms in their respective species with testoster one 2 alpha-hydroxylase activity. Comparing gender Hepatic P450 2C11 i n the rat and P450(2 alpha) in the mouse are differences, tissue distr ibution and physicochemical properties, we investigated whether this u ncommon catalytic activity shared by the two isoforms is dependent upo n a high degree of homology. Using additional substrates (e,g, androst enedione, hexobarbital), we observed that P-4502 alpha and P(450)2C11 produced no metabolites in common. Moreover, concentrations of antiser a prepared against purified P-4502 alpha that inhibited 95% of P-4502 alpha-dependent testosterone 2 alpha-hydroxylase activity had only a m inimal inhibitory effect (<20%) on P(450)2C11-dependent testosterone 2 alpha-hydroxylase and were similarly unreactive to the rat isoform is olated on Western blots. Comparison of the isoforms' N-terminal amino acid residues and two internal peptide fragments indicated almost no s equence homology (<4%). Gender-dependent tissue expression levels of P -4502 alpha and P-450 2C11 revealed additional dichotomies. Whereas he patic P-4502 alpha was moderately female-predominant (M/F; 0.62), hepa tic P(450)2C11 was clearly male-specific (M/F; 32.9). Murine P-4502 al pha mRNA was equally and substantially expressed in liver, kidney and brain; by contrast earlier studies reported that rat P-450 2C11 was ex clusively expressed in liver, The present results indicate that the un ique testosterone 2 alpha-hydroxylase activities of P-4502 alpha and P (450)2C11 are expressed by two very different proteins exhibiting mini mal homology.