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A New Form of Cytochrome P-450 Responsible for Mutagenic Activation of 2-Amino-3-methylimidazo[4,5-f]quinoline in Human Livers¹

Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060, Japan

Antibodies to P-450IA2 strongly inhibited the mutagenic activation of 2-amino-3-methylimidazo [4,5-f]quinoline (IQ) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole acetate but not aflatoxin B₁ in human liver microsomes. The anti-rat P-450IA2 antibodies were capable of recognizing two proteins which show different mobilities on sodium dodecyl sulfate-polyacrylamide gel electrophoresis of human liver microsomes. A new form of cytochrome P-450 (designated P-450-HM4) cross-reactive with anti-rat P-450IA2 antibodies showing that the smaller molecular weight was purified from human liver microsomes by means of the fast-performance liquid chromatography system. The molecular weight of P-450-HM4 was estimated to be 49,000, which was apparently different from that of P-450PA (human P-450IA2). The antibodies to P-450-HM4 did not cross-react with P-450PA (human P-450IA2) but inhibited to various extents the mutagenic activation of IQ in microsomes from human livers. In addition, P-450-HM4 showed significant mutagen-producing activity from IQ in a reconstituted system. Together with these and other results reported previously, it is concluded that at least two forms of cytochrome P-450 [P-450-HM4 and P-450PA (human P-450IA2)] are involved in the mutagenic activation of IQ in human liver.

¹ This work was partly supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan.

² Present address: Hospital Pharmacy, Chiba University Hospital, 1-8-1 Inohana, Chiba 280, Japan. To whom requests for reprints should be addressed.

Received 3/ 6/91. Accepted 12/ 3/91.