Molecular Pharmacology, Vol 13, 1181-1186, Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics

Subcellular Events Occurring during Aryl Hydrocarbon Hydroxylase Induction: No Requirement for Metabolism of Polycyclic Hydrocarbon Inducer

¹ Developmental Pharmacology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20014; Laboratoire de Chimie Médicale, Toxicologie et Hygiène, Université de Liège, B-4000 Liège, Belgium; and Laboratory of Chemistry, National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health, Bethesda, Maryland 20014

The induction of aryl hydrocarbon (benzo[a]pyrene) hydroxylase (EC 1.14.14.2) activity in the rat Reuber hepatoma H-4-II-E established cell line was studied with 3-methylcholanthrene and its K-region oxide and diol and with benzo[a]pyrene and 23 of its oxygenated derivatives, including 12 phenols, three diols, three quinones, three oxides, and two diol-epoxides. Compared with the parent benzo[a]pyrene molecule, the naturally occurring benzo[a]pyrene 6,12-quinone is approximately as potent, the chemically synthesized 12-hydroxy derivative is at least 50% more potent, and the chemically synthesized 4-hydroxy derivative is about one-half as potent in inducing the hydroxylase activity. The naturally occurring benzo[a]pyrene 7,8-oxide is also about one-half as potent as benzo[a]pyrene, and all other analogues examined are poorer inducers than the four compounds mentioned. trans-7,8-Dihydroxy-7,8-dihydrobenzo[a]pyrene is more polar than benzo[a]pyrene and enters the cells in culture more readily than benzo[a]pyrene. Knowing the amount of polycyclic hydrocarbon metabolized and the percentage of various metabolites of benzo[a]pyrene that exist in these cells, we have found no metabolite sufficiently potent to induce the hydroxylase activity more than the parent benzo[a]pyrene molecule. It is concluded, therefore, that metabolism of the parent polycyclic hydrocarbon is not a requirement for the induction process to proceed.

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ACKNOWLEDGMENTS We thank Dr. Olavi Pelkonen and Dr. Mortimer B. Lipsett for helpful suggestions in reviewing this manuscript, and Ms. Ingrid E. Jordan for her expert secretarial assistance.