Strain differences in susceptibility of normal and diabetic rats to acetaminophen hepatotoxicity.
The effects of streptozotocin (STZ)-induced diabetes on acetaminophen metabolism and hepatotoxicity in male Sprague-Dawley (SD) and Long Evans Hooded (LEH) rats were compared. In agreement with earlier studies, normal SD rats were more resistant to acetaminophen-induced hepatic necrosis than normal LEH rats. In contrast to LEH rats, the diabetic state did not protect SD rats from liver injury. Pharmacokinetic studies revealed that normal SD rats eliminated acetaminophen faster than normal LEH rats, and that the diabetic state further enhanced elimination in both strains of rats; however, the effect was much greater in LEH rats. Normal SD rats had a greater capacity to metabolize acetaminophen to nontoxic glucuronide and sulfate conjugates than normal LEH rats. In LEH rats, the diabetic state enhanced acetaminophen glucuronidation and sulfation, whereas in SD rats the diabetic state increased only sulfation; glucuronidation was unaffected. Additional studies revealed that the difference in the glucuronidation capacities between normal LEH and normal SD rats was not due to differences in either the amount of the enzyme, glucuronyl transferase, or basal hepatic levels of the cofactor, UDPGA. Similarly, the diabetes-induced enhancement of glucuronidation in LEH rats was not due to differences in predrug levels of either glucuronyl transferase or UDPGA. Thus, the major difference in susceptibility of the two strains of normal rats to acetaminophen hepatotoxicity appears to be due to the capacity to clear the drug through nontoxic pathways. The greater glucuronidation capacity seen in diabetic LEH rats and in normal and diabetic SD rats as compared to normal LEH rats, appears to be due to a greater ability to produce UDPGA in response to the metabolic demand.
Price
V F
VF
Jollow
D J
DJ
D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004198:Disease Susceptibility; D014453:Glucuronosyltransferase / Q000378:metabolism; D006207:Half-Life; D008099:Liver / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D009243:NAD / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D014532:Uridine Diphosphate Glucose / Q000378:metabolism; D014533:Uridine Diphosphate Glucose Dehydrogenase / Q000378:metabolism; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism
D009243:NAD; D014535:Uridine Diphosphate Glucuronic Acid; D000082:Acetaminophen; D014533:Uridine Diphosphate Glucose Dehydrogenase; D014453:Glucuronosyltransferase; D014532:Uridine Diphosphate Glucose