A Comparison of Cytochrome P450-Dependent Testosterone 2α-Hydroxylase in Rat (P450 2C11) and Mouse (P4502α)

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Abstract
Hepatic P450 2C11 in the rat and P4502α in the mouse are unique in being the only isoforms in their respective species with testosterone 2α-hydroxylase activity. Comparing gender differences, tissue distribution and physicochemical properties, we investigated whether this uncommon catalytic activity shared by the two isoforms is dependent upon a high degree of homology. Using additional substrates (e.g. androstenedione, hexobarbital), we observed that P4502α and P450 2C11 produced no metabolites in common. Moreover, concentrations of antisera prepared against purified P4502α that inhibited 95% of P4502α-dependent testosterone 2α-hydroxylase activity had only a minimal inhibitory effect (<20%) on P450 2C11-dependent testosterone 2α-hydroxylase and were similarly unreactive to the rat isoform isolated on Western blots. Comparison of the isoforms’ N-terminal amino acid residues and two internal peptide fragments indicated almost no sequence homology (<4%). Gender-dependent tissue expression levels of P4502α and P450 2C11 revealed additional dichotomies. Whereas hepatic P4502α was moderately female-predominant (M/F; 0.62), hepatic P450 2C11 was clearly male-specific (M/F; 32.9). Murine P4502α mRNA was equally and substantially expressed in liver, kidney and brain; by contrast earlier studies reported that rat P450 2C11 was exclusively expressed in liver. The present results indicate that the unique testosterone 2α-hydroxylase activities of P4502α and P450 2C11 are expressed by two very different proteins exhibiting minimal homology.