Molecular Pharmacology, Vol 4, 38-43, Copyright © 1968 by the American Society for Pharmacology and Experimental Therapeutics

Inhibitory Effect of 2-Diethylaminoethyl 2,2-Diphenylvalerate Hydrochloride (SKF 525-A) on Aromatic Hydroxylation and Phenolic Glucuronidation

¹ Department of Public health, Faculty of Medicine, Kyoto University, Kyoto, Japan

Kinetics of the inhibition of two microsomal enzymes of guinea pig liver by SKF 525-A was studied; namely, aryl 4-hydroxylase toward aniline and UDP-glucuronyl transferase toward phenolic glucuronidation of o-aminophenol. In vitro conversion from aniline to p-aminophenol by aryl 4-hydroxylase was noncompetitively inhibited with K_i of 1.7 x 10^-4 M, while apparent K_m of the reaction was 1.8 x 10^-3 M. Excretion of phenol or p-aminophenol in the urine of rats and guinea pigs treated with benzene or aniline, respectively, was markedly decreased by the simultaneous injection of SKF 525-A, indicating the inhibitor was effective in vivo as well as in vitro. Formation of o-aminophenyl glucuronide by UDP-glucuronyl transferase in vitro had apparent K_m of 7.1 x 10^-5 M, and was inhibited by SKF 525-A also in a noncompetitive manner with K_i of 3.6 x 10^-4 M. The in vivo effect of the inhibitor on phenolic glucuronidation was demonstrated with rats and guinea pigs.

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ACKNOWLEDGMENTS SKF 525-A was a gift from Smith, Kline and French Laboratories, Philadelphia, Pennsylvania. This work was supported in part by a grant from the Fujiwara Memorial Fund.