CYP2E1: from ASH to NASH

The pathology of the liver in alcoholic steatosis and alcoholic steatohepatitis (ASH) is remarkably similar to that of nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), suggesting some common pathogenic mechanism. Studies carried out over the last three decades of possible mechanisms involved revealed one common link, namely the induction of cytochrome P4502E1 Its substrates include fatty acids, ketones and ethanol. These substances, when present chronically in large amounts, induce the activity of the enzyme which thereby contributes to the disposition of these substrates. This reaction, however, is associated with the release of free radicals which can cause lipid peroxidation and liver injury, including mitochondrial damage. Mitochondrial damage in turn exacerbates the oxidative stress. CYP2E1 can also convert various xenobiotics to toxic metabolites. When unchecked, this toxicity eventually results in inflammation and fibrosis, culminating in cirrhosis. Prevention of this disorder is based on limiting the substrates that induce the system, such as excessive fatty acid associated with obesity and excessive alcohol consumption. No effective pharmacologic treatment is presently available but there is ongoing research on possible inhibitors of CYP2E1, innocuous enough to be suitable for chronic human consumption and sufficiently effective to attenuate the CYP2E1 induction to avoid the consequences of its excessive activity while maintaining its physiologic role. (C) 2003 Elsevier B.V. All rights reserved.