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Monoclonal Antibody-directed Analysis of Cytochrome P-450-dependent Monooxygenases and Mutagen Activation in the Livers of DBA/2 and C57BL/6 Mice¹

International Agency for Research on Cancer, 150 cours Albert-Thomas, 69372 Lyon Cedex 08, France [E. H., C. M., J-C. B., G. B., H. B.], and Laboratory of Molecular Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20205 [F. K. F., S. S. P., H. V. G.]

Monoclonal antibodies (MAb 1-7-1 and Mab 2-66-3) specific for cytochrome P-450 (cyt. P-450) isozymes inhibited the metabolism of carcinogens, other xenobiotics, and endogenous compounds in two strains of mice. Postmitochondrial liver supernatant (S9) was prepared from untreated, 3-methylcholanthrene-treated, phenobarbital-treated, and pregnenolone 16-carbonitrile-treated C57BL/6 (B6) and DBA/2 (D2) mice. The modifying effect of two types of MAb to a 3-methylcholanthrene-induced cyt. P-450 and a phenobarbital-induced cyt. P-450 was investigated for: (a) S9-mediated mutagenicity of aflatoxin B₁, benzo(a)pyrene 7,8-dihydrodiol, 2-acetylaminofluorene, and N-nitrosomorpholine in Salmonella typhimurium strains; and (b) the activity of aryl hydrocarbon hydroxylase, ethoxycoumarin O-deethylase, ethoxyresorufin O-deethylase, aminopyrine N-demethylase, and testosterone 6ß-, 7-, and 16ß-hydroxylases. With certain S9s, MAb-1-7-1 inhibited only those cytochrome P-450 isozymes involved predominantly in activity of aryl hydrocarbon hydroxylase, ethoxyresorufin O-deethylase, and ethoxycoumarin O-deethylase and mutagenicity of 2-acetylaminofluorene and benzo(a)pyrene 7,8-dihydrodiol; MAb 2-66-3 inhibited only those involved in aminopyrine N-demethylase and testosterone 6ß-, 7, and 16ß-hydroxylase activity and aflatoxin B₁ mutagenicity. Both Mab 1-7-1 and MAb 2-66-3 inhibited cytochrome P-450 isozyme(s) implicated predominantly in testosterone 7-hydroxylation in S9 from pregnenolone 16-carbonitrile-treated B6 mice. MAb 1-7-1 did not inhibit N-nitrosomorpholine mutagenicity and MAb 2-66-3 increased it by 2- to 6-fold depending on the source of S9. Using these MAbs, it is thus possible to identify the contribution of the epitope-defined single or class of cyt. P-450 to specific metabolic reactions in S9 from untreated and inducer-treated mice.

¹ Partial financial support for these studies was provided by Contract ENV-654-F (SD) with the Commission of the European Communities.

² To whom requests for reprints should be addressed.

Received 5/24/85. Revised 9/30/85. Accepted 10/17/85.