Differences in Hepatic Drug Metabolism in Various Rabbit Strains Before and After Pretreatment with Phenobarbital.

Abstract

Species variation in drug response is a well recognized pharmacological phenomenon. Strain variations within a given species, however, have been characterized to a much lesser degree. These problems assume importance not only when attempting to extrapolate results of animal experiments to man, but also in basic biological research.Law et a2( 1) have shown variations in beta-glucuronidase activity in various strains of mice. Jay(2) has also shown strain differences in mice with regard to hexobarbital sleeping time. The experiments of Yaffe(3) indicate that strain variation in drug response in mice is a genetic factor which is manifest soon after birth. Strain variation in drug response and hepatic drug metabolism in rats have been reported by Quinn et aZ(4). However, to our knowledge, no studies on strain differences in drug response have been reported using rabbits, a species commonly employed in research.We have attempted to determine whether the activity of several hepatic microsomal drug metabolizing enzyme systems varies in different rabbit strains. Studies were carried out on strains of rabbits commonly employed in research as well as on wild rabbits. We have also attempted to determine whether the stimulation of the hepatic drug metabolizing enzyme activity by phenobarbital dif-*This research was supported by a grant from Nat. Inst. Health ). fered in these strains. MateriaZs and methods. Dutch, New Zealand, English, and California strains were studied as representatives of commonly employed research animals. In addition, wild Jack rabbits were obtained from the Durant Animal Co., Ft. Sumner, New Mexico and wild Cottontails were obtained from the Earl Johnson Farms, Rago, Kansas. Rabbits were maintained on regular Purina Lab Chow and water ad libitum during the experiment, and constant conditions were maintained as nearly as possible. In all cases young adult bucks were employed.To study the effect of pre-treatment with phenobarbital, rabbits were injected intraperitoneally twice daily with 1 5 mg/kg phenobarbital sodium dissolved in normal saline. Injections were made for 3 days, on the 4th day the animals were not injected, and on the fifth day the animals were sacrificed and livers removed. Control animals were injected with normal saline on the same schedule. The livers were placed immediately on ice, blotted, weighed, and ground in the cold with a Potter homogenizer (teflon pestle) in 2 volumes of ice cold 1.15.h KCl solution. This homogenate was then centrifuged at 1-3 "C (International portable refrigerated centrifuge, model PR-2) at 9,0001 g for 30 minutes.The following metabolic pathways were studied: Side-chain oxidation of hexobarbital by guest on July 24, 2015 ebm.sagepub.com Downloaded from

A Study of the Factors Affecting the Sleeping Time Following Intracerebroventricular Administration of Pentobarbitone Sodium: Effect of Prior Administration of Centrally Active Drugs

“…This is perhaps indicative of an increased drug sensitivity in female rats. Strain differences in drug-metabolizing enzyme activity have been reported with rabbits (Cram, Juchau & Fouts, 1965) and rats (Mitoma, Neubauer, Badger & Sorich, 1967;Jori et al, 1971). Stress has been reported to stimulate metabolism of, and reduce the response to, hexobarbitone, pentobarbitone and meprobamate.…”

Genetic control of the phenobarbital-induced shortening of plasma antipyrine half-lives in man

“…By changing rates of drug metabolism in hepatic microsomes, numerous factors may substantially modify the duration and intensity of action of various therapeutic agents. Although genetic, dietary, hormonal, and nutritional causes of alterations in the drug-metabolizing activities of hepatic microsomes have been investigated, particular attention has focused on certain foreign compounds that augment these activities (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11) degree of shortening of antipyrine half-life by phenobarbital appear to be independent of absolute blood levels of phenobarbital.…”

TCDD-Induced Changes in Rat Liver Microsomal Enzymes

“…However, TCDD appears not to shift the peak in the carbon monoxide difference spectra from 450 nm to 448 nm such as occurs with 3-methylcholanthrene induction (26). TCDD obviously cannot be considered a phenobarbital-type inducer, which is characterized by increased P-450 content, increased hydroxylation activity, and increased oxidative N-demethylation (27).…”