Cytochrome liver disease

Hypersensitivity to benzodiazepines psychoses acute narrow-angle glaucoma patients with clinical or biochemical evidence of significant liver disease intra-arterial use (lorazepam injection) children younger than 6 months of age, lactation (diazepam) coadministration with ketoconazole and itraconazole caused by inhibition of cytochrome P450 3A. 

Most drugs used in anaesthesia are metabolised in the liver by phase I reactions, mediated by cytochrome P-450 enzymes. These are susceptible to destruction by cirrhosis, so that the biotransformation of drugs, such as opioids (except morphine), benzodiazepines, barbiturates, and inhalational agents, may be markedly altered in severe liver disease. These enzymes are found in the centrilobular areas, which are more prone to hypoxia. In contrast, the enzymes responsible for phase II reactions, found predominantly in the peripheral areas, often function normally even in advanced disease. The disposition of benzodiazepines that are eliminated primarily by glucuronidation, e.g. lorazepam and oxazepam, are unaffected by chronic liver disease. For drugs with low hepatic extraction, advanced hepatocytic dysfunction decreases phase I and II biotransformation with a reduced clearance and prolongation of the elimination half-life. This is often partially offset by an increased free fraction due to decreased protein binding. 

NO also has cytotoxic effects when synthesized in large quantities, eg, by activated macrophages. For example, NO inhibits metalloproteins involved in cellular respiration, such as the citric acid cycle enzyme aconitase and the electron transport chain protein cytochrome oxidase. Inhibition of the heme-containing cytochrome P450 enzymes by NO is a major pathogenic mechanism in inflammatory liver disease. 

Disease/pathological conditions. Disposition of chemicals is potentially altered by disease and hence toxicity. Generalization, however, is difficult as the effects are unpredictable. Thus liver disease may decrease metabolism, but this depends on type of disease and particular pathway of metabolism. Disease in one organ may affect the response of another, for example, chronic renal disease decreases hepatic cytochrome P-450. 

Yang LQ, Li SJ, Cao YF, et al. Different alterations of cytochrome P450 3A4 isoform and its gene expression in livers of patients with chronic liver disease. World J Gastroenterol. 2003 9 359-363. 

Horsmans, Y. Major cytochrome P450 families implications in health and liver disease. Acta Gastro-Enterol. Belg. 15 (1997) 2-10. 

Kato S, Onda M, MatsukuraN. 1995. Cytochrome p4502El (CYP2E1) genetic polymorphism in a case-control study of gastric cancer and liver disease. Pharmacogenetics 5 141-144. 

Villeneuve JP, Pichette V (2004) Cytochrome P450 and liver diseases. Curr Drug Metab 5 273-282. 

George J, Murray M, Byth K, et al. (1995) Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease. 

Adedoyin A, Arns PA, Richards WO, et al. (1998) Selective effect of liver disease on the activities of specific metabolizing enzymes investigation of cytochromes P450 2C19 and 2D6. Clin Pharmacol Ther 64 8-17. 

Frye RF, Zgheib NK, Matzke GR, et al. (2006) Liver disease selectively modulates cytochrome P450-mediated metabolism. Clin Fharmacol Ther 80 235-245. 

Chronic alcohol consumption can induce CYP450 enzymes, whereas acute alcohol intake can inhibit cytochrome P450 enzymes. Prediction of drug handling in alcoholic liver disease is therefore complicated. 

Cirrhosis occurs most frequently in the setting of alcoholic liver disease and represents the final common pathway of a number of chronic liver diseases. The development of cirrhosis is characterized by the appearance of fibroblasts and collagen deposition. This is accompanied by a reduction in liver size and the formation of nodules of regenerated hepatocytes. As a result, total liver content of cytochrome P450 is reduced in these patients. Initially, fibroblasts deposit collagen fibrils in the sinusoidal space, including the... 

Thiele GM, Tuma DJ, Willis MS, Vidali M, Stewart SF, Rolla R, Daly AK, Chen Y, Mottaran E, Jones DE, Leatherhart JB, Day CP, Albano E (2003) Genetic and epigenetic factors in autoimmune reactions toward cytochrome P4502E1 in alcoholic liver disease. Hepatology, 37 410-419. 

M. Ingelman-Sundberg, K.O. Lindros, PC. Fu et al. (1993). Role of cytochrome P4502E1 in alcoholic liver disease pathogenesis. Alcohol 10, 459 64. 

Horsmans, Y. 1997. Major cytochrome P450 families Implications in health and liver diseases. Acta Gastroenterologica Belgique 60 2-10. 

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