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SA Wrighton, BJ Ring, PB Watkins and M VandenBranden
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226.
The human liver cytochrome P-450III family contains two highly related forms of cytochrome P-450 (P450), HLp and P450NF, that are expressed in the adult and a form, HLp2, that is expressed in the fetus. Immunoblot analyses of 46 liver specimens developed with an anti-HLp antibody demonstrated that, in addition to HLp, 11 specimens contained a previously undected higher molecular weight protein (termed HLp3). The expression of HLp3 did not correlate with the age, gender, smoking habits, or drug history of the patients. This protein was purified and found to be a P450 with a molecular weight of 52,000. Ouchterlony analyses using a polyclonal anti-HLp antibody yielded lines of partial identity between HLp3 and both HLp and HLp2. In addition, structural comparisons between these three proteins, including amino-terminal amino acid analyses and peptide mapping, indicated that HLp3, HLp2, and HLp are highly related but distinct proteins. In reconstituted systems, HLp and HLp3 were found to hydroxylate testosterone at the 6 beta and 2 beta positions. In microsomes, the rates of hydroxylation of testosterone at the 2 beta, 6 alpha, 6 beta, 15 beta, and 18 positions and the formation of an unknown were found to correlate with the levels of total HLp-related protein and these activities were inhibited by anti-HLp antibodies. In conclusion, our data demonstrate that HLp3 is a member of the human P450III family and is polymorphically expressed.
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