ALCOHOL: its metabolism and interaction with nutrients.
In the past, alcoholic liver disease was attributed exclusively to dietary deficiencies, but experimental and judicious clinical studies have now established alcohol's hepatotoxicity. Despite an adequate diet, it can contribute to the entire spectrum of liver diseases, mainly by generating oxidative stress through its microsomal metabolism via cytochrome P4502E1 (CYP2E1). It also interferes with nutrient activation, resulting in changes in nutritional requirements. This is exemplified by methionine, one of the essential amino acids for humans, which needs to be activated to S-adenosylmethionine (SAMe), a process impaired by liver disease. Thus, SAMe rather than methionine is the compound that must be supplemented in the presence of significant liver disease. In baboons, SAMe attenuated mitochondrial lesions and replenished glutathione; it also significantly reduced mortality in patients with Child A or B cirrhosis. Similarly, decreased phosphatidylethanolamine methyltransferase activity is associated with alcoholic liver disease, resulting in phosphatidylcholine depletion and serious consequences for the integrity of membranes. This can be offset by polyenylphosphatidylcholine (PPC), a mixture of polyunsaturated phosphatidylcholines comprising dilinoleoylphosphatidylcholine (DLPC), which has high bioavailability. PPC (and DLPC) opposes major toxic effects of alcohol, with down-regulation of CYP2E1 and reduction of oxidative stress, deactivation of hepatic stellate cells, and increased collagenase activity, which in baboons, results in prevention of ethanol-induced septal fibrosis and cirrhosis. Corresponding clinical trials are ongoing.
Lieber
C S
CS
Mount Sinai School of Medicine and Alcohol Research and Treatment Center, Section of Liver Disease and Nutrition, Bronx Veterans Affairs Medical Center, Bronx, New York 10468, USA. liebercs@aol.com
D000426:Alcohol Dehydrogenase / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D001361:Avitaminosis / Q000209:etiology / Q000378:metabolism; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004032:Diet; D004035:Diet Therapy; D000431:Ethanol / Q000009:adverse effects / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000378:metabolism* / Q000517:prevention & control / Q000628:therapy; D009752:Nutritional Status / Q000502:physiology*; D018384:Oxidative Stress; D012436:S-Adenosylmethionine / Q000008:administration & dosage / Q000172:deficiency
D000975:Antioxidants; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D000431:Ethanol; D012436:S-Adenosylmethionine; D000426:Alcohol Dehydrogenase