Effects of model traumatic injury on hepatic drug metabolism in the rat. III. Differential responses of cytochrome P-450 subpopulations.
A previously validated small mammal trauma model, hind-limb ischemia secondary to infrarenal aortic ligation in the rat, was utilized to further investigate the effects of traumatic injury on the hepatic cytochromes P-450. In vitro drug metabolism studies with hexobarbital and zoxazolamine as substrates confirmed the post-traumatic depression of the cytochrome P-450-catalyzed oxidation of these drugs which was suggested by previous in vivo pharmacokinetic studies. Enzyme kinetic studies revealed diminished Vmax values with no change in Km, a finding which would seem to concur with the previously demonstrated decrease in hepatic cytochrome P-450 content after model trauma. Moreover, a battery of in vitro microsomal monooxygenase assays demonstrated that model trauma exerted a differential effect on various hepatic cytochrome P-450 isoenzymes. This phenomenon was confirmed by anion-exchange HPLC of solubilized hepatic microsomal hemoproteins. One of the most interesting aspects of this selective effect on cytochrome P-450 subtypes was the relative induction of cytochrome P-448 content and activity, in contrast to the variable decrease seen with cytochrome P-450 activities. The potential in vivo sequelae of this differential influence were suggested by changes observed in the urinary metabolic profile of antipyrine after model trauma.
D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D000815:Aniline Hydroxylase / Q000378:metabolism; D000818:Animals; D000983:Antipyrine / Q000652:urine; D001571:Benzoflavones / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004195:Disease Models, Animal; D005037:Ethylmorphine-N-Demethylase / Q000378:metabolism; D006591:Hexobarbital / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D009575:Nitroanisole O-Demethylase / Q000378:metabolism; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D014947:Wounds and Injuries / Q000378:metabolism*; D015049:Zoxazolamine / Q000378:metabolism; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D004364:Pharmaceutical Preparations; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D015049:Zoxazolamine; D006591:Hexobarbital; D009575:Nitroanisole O-Demethylase; D010088:Oxidoreductases; D000815:Aniline Hydroxylase; D019363:Cytochrome P-450 CYP1A1; D000633:Aminopyrine N-Demethylase; D005037:Ethylmorphine-N-Demethylase; D000983:Antipyrine; D010634:Phenobarbital