Submitted to: Critical Reviews in Toxicology
Publication Type: Review Article
Publication Acceptance Date: 3/15/2007
Publication Date: 5/5/2007
Citation: Wang, T., Shankar, K., Ronis, M.J., Mehendale, H.M. 2007. Mechanisms and outcomes of drug- and toxicant-induced liver toxicity in diabetes. Critical Reviews in Toxicology. 37(5):413-459.
Interpretive Summary: Diabetes is a disease that if gone untreated will ultimately result in death. Importantly, however, many diabetic patients also have other conditions requiring medication. The combined incidence of diabetes and certain drugs can be toxic to the liver. This article describes results from studies using rats to reproduce the diabetes and drug combinations that produce liver toxicity and explains how the liver deals with these problems. The results from such studies will be useful in developing either non-toxic drugs for diabetics or ways to reduce liver toxicity in diabetes.
Technical Abstract: Increase incidences of hepatotoxicity have been observed in diabetic patients receiving drug therapies. Neither the mechanisms nor the predisposing factors underlying hepatotoxicity in diabetics are clearly understood. Animal studies designed to examine the mechanisms of diabetes-modulated hepatotoxicity have traditionally focused only on bioactivation/detoxification of drugs and toxicants. It is becoming clear that once injury is initiated, additional events determine the final outcome of liver injury. Foremost among them are two leading mechanisms: first, biochemical mechanisms that lead to progression or regression of injury; and second, whether or not timely and adequate liver tissue repair occurs to mitigate injury and restore liver function. The liver has a remarkable ability to repair and restore its structure and function after physical or chemical-induced damage. The dynamic interaction between biotransformation-based liver injury and compensatory tissue repair plays a pivotal role in determining the ultimate outcome of hepatotoxicity initiated by drugs or toxicants. In this review, mechanisms underlying altered hepatotoxicity in diabetes with emphasis on both altered bioactivation and liver tissue repair are discussed. Animal models of both marked sensitivity (diabetic rats) and equally marked protection (diabetic mice) from drug-induced hepatotoxicity are described. These examples represent a remarkable species difference. Availability of the rodent diabetic models offers a unique opportunity to uncover mechanisms of clinical interest in averting human diabetic sensitivity to drug-induced hepatotoxicities. While the rat diabetic models appear to be suitable, the diabetic mouse models might not be suitable in preclinical testing for potential hepatotoxic effects of drugs or toxicants, because regardless of type 1 or type2 diabetes, mice are resistant to acute drug-or toxicant-induced toxicities.