RT Journal Article
SR Electronic
T1 Subcellular Events Occurring during Aryl Hydrocarbon Hydroxylase Induction: No Requirement for Metabolism of Polycyclic Hydrocarbon Inducer
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1181
OP 1186
VO 13
IS 6
A1 ITSU KANO
A1 JACQUES E. GIELEN
A1 HARUHIKO YAGI
A1 DONALD M. JERINA
A1 DANIEL W. NEBERT
YR 1977
UL http://molpharm.aspetjournals.org/content/13/6/1181.abstract
AB 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. 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.