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ARS Home » Southeast Area » Little Rock, Arkansas » Microbiome and Metabolism Research Unit » Research » Publications at this Location » Publication #164998
Title: TYPE 1 DIABETIC MICE ARE PROTECTED FROM ACETAMINOPHEN HEPATOTOXICITY

Author
item SHANKAR, KARTIK - UAMS
item VAIDYA, VISHAL - UNIV OF LA/MONROE
item APTE, UDAYAN - UNIV OF LA/MONROE
item MANAUTOU, JOSE - UNIV OF CONNECTICUT
item RONIS, MARTIN - UAMS
item BUCCI, THOMAS - NCTR
item MEHENDALE, HARIHARA - UNIV OF LA/MONROE

Submitted to: Toxicological Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/7/2003
Publication Date: 4/15/2003
Citation: Shankar, K., Vaidya, V.S., Apte, U.M., Manautou, J.E., Ronis, M.J., Bucci, T.J., Mehendale, H.M. 2003. Type 1 diabetic mice are protected from acetaminophen hepatotoxicity. Toxicological Sciences. 73(2):220-234.

Interpretive Summary: A serious side effect of some drugs used to treat diabetes, for example troglidazone, is liver damage. It has been suggested that part of the problem is that the liver of diabetics is more susceptible to damage from drugs and environmental chemicals than is normal liver. This idea is supported by results from many studies of liver damage in rats made diabetic with the drug streptozotocin. However, there appears to be a major species difference in this effect between rats and mice. We have demonstrated in the current study that in contrast to the rat (and presumably human diabetics), diabetic mice are protected against death from liver damage produced by several drugs and chemicals including acetaminophen (Tylenol), carbon tetrachloride and bromobenzene. We have examined the mechanism of this protection to gain a better understanding of the species difference and to increase our understanding of what happens in the liver of human diabetics. We demonstrated that in the diabetic mouse, acetaminophen is both removed more quickly from the circulation as the result of increased urine production and decreased production of the liver enzymes (CYP2E1 and CYP1A2) which metabolize acetaminophen to a chemical that produces liver damage.Why then do diabetic mice survive and untreated mice die of liver failure? Our results suggest that the answer appears to lie in increased ability of the diabetic mouse liver to repair itself from injury.

Technical Abstract: Streptozotocin (STZ)-induced diabetic (DB) mice challenged with single ordinarily lethal doses of acetaminophen (APAP), carbon tetrachloride (CCl4), or bromobenzene (BB) were resistant to all three hepatotoxicants. Mechanisms of protection against APAP hepatotoxicity were investigated. Plasma alanine aminotransferase, aspartate aminotransferase, and liver histopathology revealed significantly lower hepatic injury in DB mice after APAP administration. HPLC analysis of plasma and urine revealed lower plasma t1/2, increased volume of distribution (Vd), and increased plasma clearance (CLp) of APAP in the DB mice and no difference in APAP-glucuronide, a major metabolite in mice. Interestingly, covalent binding of 14C-labeled APAP to liver target proteins; arylation of APAP to 58, 56, and 44 kDa acetaminophen binding proteins (ABPs); and glutathione (GSH) depletion in the liver did not differ between nondiabetic (non-DB) and DB mice in spite of downregulated hepatic microsomal CYP2E1 and 1A2 proteins in the DB mice, known to be involved in bioactivation of APAP. Compensatory cell division measured via 3H-thymidine pulse labeling and immunohistochemical staining for proliferating cell nuclear antigen (PCNA) indicated earlier onset of S-phase in the DB mice after exposure to APAP. Antimitotic intervention of liver cell division by colchicine (CLC) after administration of APAP led to significantly higher mortality in the DB mice suggesting a pivotal role of liver cell division and tissue repair in the protection afforded by diabetes. In conclusion, the resistance of DB mice against hepatotoxic and lethal effects of APAP appears to be mediated by a combination of enhanced APAP clearance and robust compensatory tissue repair. Key Words: covalent binding; CYP2E1; diabetes; species differences; tissue repair.