Obesity decreases hepatic glutathione concentrations and markedly potentiates allyl alcohol-induced periportal necrosis in the overfed rat.
Liver biopsies from 9 out of every 10 obese individuals exhibit pathological changes of unknown aetiology and 3 out of every 10 reflect severe injury in the form of periportal fibrosis. To examine the hypothesis that excessive fibrosis in obesity arises in part from a predisposition to injury of the liver by drugs and xenobiotics, we administered 5, 10 and 25 mg/kg doses of the model periportal hepatotoxin, allyl alcohol, to obese Sprague-Dawley rats and age-matched non-obese controls. Alanine aminotransferase activity (ALT) in plasma was ten-fold more elevated in obese animals than in non-obese animals given the 25 mg/kg dose (P < 0.05). On fitting the ALT results to a non-linear, parametric model by iterative non-linear least squares regression, we found that the slope of the log dose ALT curve was similar for obese and non-obese rats. However, the minimum dose required to produce elevated ALT (DMIN) was 50% lower for obese animals (DMIN 6.47 +/- 2.75 vs. 13.3 +/- 0.96 mg allyl alcohol; P < 0.05). In a subsequent experiment, allyl alcohol was administered to obese rats based on ideal body weight, which is defined as the mean total body weight of an age-matched non-obese animal. With this dosing normalization, the 25 mg/kg ideal body weight doses translated to administration of a fixed dose of 13.5 mg allyl alcohol to obese rats. Obese rats treated in this fashion exhibited more severe necrosis in the periportal zone (median necrosis score 2 versus 0-1, P < 0.05) and increased mortality over controls (44% versus 0%; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Salazar
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DE
Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo 14260.
Sorge
C L
CL
Jordan
S W
SW
Corcoran
G B
GB
D000433:1-Propanol / Q000633:toxicity; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D005978:Glutathione / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000209:etiology*; D008297:Male; D009336:Necrosis; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D020005:Propanols; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
D020005:Propanols; C006463:allyl alcohol; D000433:1-Propanol; D000410:Alanine Transaminase; D005978:Glutathione