Protective Effects of Diallyisulfide, Taurin, and Quercetion against Drug Induced Hepatoxicity, Associated with Methimazole, Amodiaquine, Hydralazine and Isoniazid in Rat Hepatocytes

Abstract

The liver is very active in metabolizing foreign compounds and is a major target for toxicity caused by chemicals. On the exposure to xenobiotics, the liver of vertebrates manages to eliminate such foreign compounds as early as possible. This is accomplished by making use of the normally existing biochemical mechanisms in the tissue. Certain enzymes and other endogenous biomolecules, which are actually meant for the metabolism of endogenous substrates, may be utilized for this purpose. Biotransformation of a xenobiotic compound following its exposure can alter its distribution and action, leading to its detoxification and excretion and/or enhance its toxicity due to the activation of the compound. Therefore, hepatotoxicity may be the result of the drug action itself or, more frequently, a result of the bioactivation process and the production of reactive metabolites. Prioritization of compounds based on human hepatotoxicity potential is currently a key requirement in drug discovery, as it can become a major problem for several lead compounds in later stages of the drug discovery process. Therefore, evaluation of the potential hepatotoxicity of drugs and revealing their mechanisms of toxicity represents a critical step in the development of new drugs and guiding and accelerating the development of safer pharmaceuticals. In addition, elucidation of mechanisms of toxicity is one of the most important bridges connecting hazard detection with risk assessment for human health, ultimately leading to toxicity prediction, treatment, and prevention. Isolated hepatocytes are increasingly used by the scientists for the screening of hepatotoxic potential of drugs and other xenobiotics. Hepatocytes in suitable environment retain hepatic key functions and constitute a valuable tool to identify chemically induced cellular damage. Their use has notably contributed to the understanding of mechanisms responsible for hepatotoxicity (disruption of cellular energy status, alteration of Ca2+ homeostasis, inhibition of transport systems, metabolic activation, oxidative stress, covalent binding, etc.). Studies on isolated hepatocytes will identify potential adverse effects of drugs on the liver and help to elucidate their mechanism(s). With the ever-increasing exposure to pharmaceuticals, more and more examples of drug induced liver disease have been identified in recent years and drug-induced liver injuries (DILI) represent an important problem. Drug-induced liver disease is the most common cause of acute liver failure, accounting for one-third to one-half of cases; although acetaminophen accounts for the majority of these, other drugs are still more frequent causes of the acute liver failure than viral hepatitis and other causes. In this thesis, we selected some drugs from different chemical groups (Methimazole, Isoniazid, Amodiaquine, and Hydralazine) that hepatotoxicity is one of their most deleterious adverse effects.