Molecular Pharmacology, Vol 14, 145-154, Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics

Microsomal Biphenyl Hydroxylation: the Formation of 3-Hydroxybiphenyl and Biphenyl Catechol

¹ Lilly Research Laboratories, Indianapolis, Indiana 46206

3-Hydroxybiphenyl has been identified as a metabolite of biphenyl incubated with liver microsomes. Liver microsomes from hamster, mouse, and rabbit form 3-hydroxybiphenyl as well as 2-hydroxybiphenyl and 4-hydroxybiphenyl. The ratio of 2-hydroxybiphenyl to 3-hydroxybiphenyl is about 2:l with hamster and rabbit microsomes and 1:l with mouse microsomes. The major metabolite in all three species is 4-hydroxybiphenyl, but its relative amount also depends upon the species. Control rat liver microsomal hydroxylation of biphenyl yields 4-hydroxybiphenyl almost exclusively. 3-Methylcholanthrene or -napthoflavone treatment of rats preferentially induces 2-hydroxybiphenyl formation, whereas increased amounts of 3- and 4-hydroxybiphenyl are formed after administration of phenobarbital. These results indicate that 3-hydroxybiphenyl is formed by a pathway different from that of either 2- or 4-hydroxybiphenyl. The existence of isotope effects for 3-hydroxybiphenyl formation but not for 2- or 4-hydroxybiphenyl formation from perdeuterobiphenyl suggests that this hydroxylation occurs at least partially via a direct hydroxylation pathway. In addition to the monohydroxylated products of biphenyl, the microsomal oxidation of biphenyl yields the catechol, 3,4-dihydroxybiphenyl. This same catechol is produced by the hydroxylation of either 3- or 4-hydroxybiphenyl. Studies with ¹⁸O suggest that 3,4-dihydroxybiphenyl is formed from biphenyl via two consecutive hydroxylations.

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ACKNOWLEDGMENTS The authors thank Dr. Donald Jerina of the National Institutes of Health for encouraging us to extend his earlier work on the isotope effects in the hydroxylation of biphenyl, since the work which he and his co-workers performed some years ago was hampered by the lack of suitable analytical procedures at that time. The authors are indebted to Mr. Gary Whitaker for expert technical assistance throughout the course of these studies.