DIPHENYLHYDANTOIN METABOLISM BY RAT LIVER MICROSOMES AND SOME OF THE EFFECTS OF DRUG OR CHEMICAL PRETREATMENT ON DIPHENYLHYDANTOIN METABOLISM BY RAT LIVER MICROSOMAL PREPARATIONS

¹ Department of Pharmacology, College of Medicine, University of Iowa, Iowa City, Iowa

The apparent V_max of diphenylhydantoin (DPH) metabolism by washed rat liver microsomes was approximately one-half of that obtained with 9000 x g supernatant fraction, whereas the apparent K_m was the same for both fractions (3 x 10^-5 M). The 100,000 x g supernatant seemed to contain factors that served as co-factors for the microsomal DPH metabolism and also prevented rapid decay of microsomal DPH-metabolizing enzyme activity. Pretreatment of rats with phenobarbital, chlordane or dichlorodiphenyltrichloroethane (DDT) moderately increased the apparent V_max for DPH metabolism and alightly increased the apparent K_m. DPH treatment for up to seven days had no effect and 3-methylcholanthrene (3-MC) treatment decreased the rate of DPH metabolism by microsomes from treated animals. Addition of chlordane, DDT or 3-MC in 10^-5 M concentrations to incubation mixtures containing microsomes from control animals reduced DPH metabolism by 20 to 50%. The A_max of substrate-induced difference spectra caused by the addition of DPH to microsomal suspensions was decreased in the microsomes from the animals treated with phenobarbital, DPH, chlordane, DDT or 3-MC as compared with microsomes from control animals. Addition of these enzyme-inducing agents in 10^-5 M concentrations to microsomes from untreated or control animals decreased the A_max DPH-microsome difference spectra, and higher concentrations of these chemicals abolished the difference spectra completely. It may be concluded that DPH binds only weakly to liver microsomes despite its low apparent K_m and K_s values.

This article has been cited by other articles:

				T. Izumi, K. Hosiyama, S. Enomoto, K. Sasahara, and Y. Sugiyama Pharmacokinetics of Troglitazone, an Antidiabetic Agent: Prediction of In Vivo Stereoselective Sulfation and Glucuronidation from In Vitro Data J. Pharmacol. Exp. Ther., March 1, 1997; 280(3): 1392 - 1400. [Abstract] [Full Text]