Cytochrome P450 induction by phenobarbital exacerbates warm hepatic ischemia-reperfusion injury in rat livers.
Recent studies have shown that cytochrome P450 inhibitors reduce oxidative stress and injury to the liver following warm ischemia-reperfusion (IR). The aim here was to test the effect of P450 induction by phenobarbital on the IR injury in rat livers. Rats were pre-treated with saline or phenobarbital and subjected to IR or sham operation. IR significantly increased the plasma alanine aminotransferase concentrations. Phenobarbital further exacerbated the injury by an additional 50% increase in the alanine aminotransferase levels. Phenobarbital also caused an approximately 40% increase in the total P450 content of the liver, which was also associated with a 75% increase in the reactive oxygen species (ROS) generation in the IR group. There was a strong correlation between the microsomal ROS generation and total P450 content, CYP3A2 activity or CYP2B1 activity. It is concluded that the induction of P450 by phenobarbital significantly increases hepatic production of ROS, leading to significantly higher hepatic IR injury.
Shaik
Imam H
IH
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA.
Mehvar
Reza
R
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D015415:Biomarkers / Q000097:blood; D002374:Catalase / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis*; D051544:Cytochrome P-450 CYP3A; D004195:Disease Models, Animal; D004790:Enzyme Induction; D005978:Glutathione / Q000378:metabolism; D006418:Heme / Q000378:metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008107:Liver Diseases / Q000201:enzymology* / Q000209:etiology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D008862:Microsomes, Liver / Q000201:enzymology; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D018384:Oxidative Stress; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology* / Q000209:etiology; D013482:Superoxide Dismutase / Q000378:metabolism; D052096:Warm Ischemia / Q000009:adverse effects*
D015415:Biomarkers; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D006418:Heme; D002374:Catalase; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D013482:Superoxide Dismutase; D009251:NADPH-Ferrihemoprotein Reductase; D000410:Alanine Transaminase; D005978:Glutathione; D010634:Phenobarbital