Obesity as a risk factor for drug-induced organ injury. VI. Increased hepatic P450 concentration and microsomal ethanol oxidizing activity in the obese overfed rat.
The obese overfed rat effectively models many of the pharmacological changes in human obesity. Recent data show that the obese rat is unusually susceptible to liver damage by several metabolically activated drugs that may be more toxic in obese humans. Results of the present study suggest a specific molecular locus for this interaction. In obese rats, P450 content of liver and the microsomal concentration of P450 were elevated 88% and 31%, respectively, over nonobese controls. Increases in microsomal ethanol oxidation were of identical magnitude. The ethanol-inducible form of P450 that is responsible for microsomal ethanol oxidation, P450IIE1, bioactivates several drugs that are shown to cause increased injury in obese rats. Collectively, these findings indicate that specific forms of P450 may become up-regulated in obesity, increasing the risk of a biochemically defined spectrum of drug-induced organ injuries.
Salazar
D E
DE
Department of Pharmaceutics, School of Pharmacy, State University of New York, Buffalo 14260.
Sorge
C L
CL
Corcoran
G B
GB
D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000431:Ethanol / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009765:Obesity / Q000201:enzymology*; D010084:Oxidation-Reduction; D051381:Rats; D012307:Risk Factors
D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D000426:Alcohol Dehydrogenase; D000444:Aldehyde Dehydrogenase