Molecular Pharmacology, Vol 20, 662-668, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

Specificity of Rabbit Pulmonary Cytochrome P-450 Isozymes in the Activation of Several Aromatic Amines and Aflatoxin B₁

¹ Laboratory of Molecular Genetics and Laboratory of Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

The involvement of pulmonary or hepatic cytochrome P-450 monooxygenase enzymes in the activation of the promutagens 2-aminoanthracene, 2-aminofluorene, 2-acetylaminofluorene, and aflatoxin B₁ has been investigated using Salmonella strain TA98. These agents were more readily metabolized to mutagenic products by the 16,000 x g supernatant fraction from lung than from liver despite the low pulmonary cytochrome P-450 content, and more revertants per nanomole of total cytochrome P-450 were consistently obtained with pulmonary than with hepatic microsomal preparations. In reconstituted monooxygenase systems containing the major pulmonary cytochrome P-450 isozymes (P-450_I or P-450_II), P-450_II was highly effective in the activation of 2-aminoanthracene and 2-aminofluorene and also active with 2-acetylaminofluorene, whereas these substrates were not activated by P-450_I. This difference was confirmed by the results of antibody inhibition studies carried out with pulmonary microsomal preparations. The higher activity of pulmonary preparations relative to hepatic preparations can be accounted for by the relatively high proportion of P-450_II in the lung (approximately 50% total cytochrome P-450 content) as compared with the liver (less than 5%). However, antibody to P-450_II did inhibit the hepatic microsomal activities by 50-70%, indicating that P-450_II may be important in the activation of these agents in both tissues even though it is a minor component in the liver. Aflatoxin B₁ was activated only by P-450_I in reconstituted monooxygenase systems, although the antibody inhibition studies indicated activation by both P-450_I and P-450_II in pulmonary microsomal preparations.

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ACKNOWLEDGMENTS We gratefully thank Mr. Zadock McCoy and Ms. Barbara Bynum for their expert assistance.