DIPHENYLHYDANTOIN EFFECT ON NEONATAL AND ADULT RAT HEPATIC DRUG METABOLISM

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

Diphenylhydantoin (DPH) treatment increased hepatic drug metabolism of 5-and 10-day-old neonatal rats. In vitro metabolism was measured using the 9000 x g supernatant fraction as the enzyme source. Neonatal hepatic metabolism of p-nitroanisole, hexobarbital, benzphetamine, aminopyrine and -nitrobenzoic acid was significantly increased by DPH treatment. DPH treatment increased neonatal liver weight, but did not alter microsomal protein content per gram of liver or the ability of the 9000 x g supernatant fraction to generate reduced nicotinamide adenine dinucleotide phosphate (NADPH). Likewise, DPH treatment of adult rats significantly increased hepatic metabolism of benzphetamine and aminopyrine. Regardless of animal age, aniline hydroxylase and benzpyrene hydroxylase were apparently unaffected by DPH treatment. The amount of hepatic microsomal cytochrome P-450 was significantly increased, but cytochrome b₅ was unaffected by DPH treatment of all age groups. Rat liver microsomal P-450 was qualitatively unchanged by DPH treatment or at different animal ages, as demonstrated by unaltered "cross-over point"—the pH at which the peak heights at 455 mµ and 430 mµ were equal in the ethyl isocyanide-induced difference spectra of dithionite-reduced hepatic microsomes. This ethyl isocyanide cross-over point in control animals was similar at all ages.