European Journal of Biomedical and Pharmaceutical Sciences

MOLECULAR MECHANISMS OF LIVER INJURY INDUCED BY HEPATOTOXINS

Dr. S. Gopinathan*

ABSTRACT

Liver is a vital organ and plays a major role in detoxification and excretion of many toxic chemicals (hepatotoxins). To detoxify the hepatotoxins liver cells operate various metabolic pathways involving different enzyme systems. During this process different kinds of toxic free radicals and electrophiles are produced and these molecules are responsible for the liver injury that leads to hepatic dysfunction. The pathways and the molecular mechanisms involved during the pathogenesis of liver injury due to abuse of paracetamol (acetaminophen), alcohol, carbon tetrachloride (CCl4), and N-nitrosodiethylamine (NDEA or DEN) and N-nitrosodimethylamine (NDMA) are reviewed in this article to understand their adverse cellular reactions which are useful in devising new modalities for the treatment of liver injury induced by hepatotoxins. Metabolism of paracetamol involves glucuronidation (UDP-glucuronosyl transferases), sulfation (sulfotransferases) and deacetylation (N-deacetylase) pathways. At higher doses, cytochrome P450 (CYP2E1) enzyme system is involved and a toxic metabolite namely N-acetyl-p-benzoquinone imine (NAPQI) is produced. In alcohol metabolism, alcohol dehydrogenase and aldehyde dehydrogenase enzyme systems are implicated and acetaldehyde, a highly toxic molecule is formed during the reaction. When alcohol is consumed at large quantity CYP2E1 enzyme system is activated and resulted in the production of ROS such as superoxide (O2• −), hydroxyl radical (OH.) and hydrogen peroxide (H2O2) and other free radicals. CCl4 metabolism is catalyzed by CYP2E1enzyme system and the reaction ends with the production of highly toxic free radicals such as trichloromethyl radical (CCl3*) and trichloromethyl peroxy radical (CCl3OO*). Metabolism of NDEA and NDMA involves alpha-hydroxylation pathway which produce hydroxymethylnitrosamine and it is further transformed into diazohydroxide and formaldehyde. The in vivo antioxidant molecules particularly reduced glutathione (GSH) are involved in the detoxification of free radicals. When detoxification process fails, the toxic intermediate metabolites can potentially alter the structure and function of cellular macromolecules, leading to apoptosis and/or necrosis and establish the liver injury.

Keywords: Liver injury, hepatotoxins, molecular mechanisms, paracetamol, carbon tetrachloride, alcohol, N-nitrosoamines.