ubiquinone and Liver-Cirrhosis--Alcoholic

The isoprenoid pathway produces three key metabolites--endogenous digoxin (modulate tryptophan/tyrosine transport), dolichol (important in N-glycosylation of proteins), and ubiquinone (free radical scavenger). It was considered pertinent to assess the pathway in alcoholic addiction, alcoholic cirrhosis, and acquired hepatocerebral degeneration. Since endogenous digoxin can regulate neurotransmitter transport, the pathway and the related cascade were also assessed in individuals with differing hemispheric dominance to find out the role of hemispheric dominance in its pathogenesis. In the patient group there was elevated digoxin synthesis, increased dolichol and glycoconjugate levels, and low ubiquinone and elevated free radical levels. There was also an increase in tryptophan catabolites and a reduction in tyrosine catabolites, as well as reduced endogenous morphine synthesis from tyrosine. There was an increase in cholesterol:phospholipid ratio and a reduction in glycoconjugate level of RBC membrane in these groups of patients. Alcoholic cirrhosis, alcoholic addiction, and acquired hepatocerebral degeneration are associated with an upregulated isoprenoid pathway and elevated digoxin secretion from the hypothalamus. This can contribute to NMDA excitotoxicity and altered connective tissue/lipid metabolism important in its pathogenesis. Endogenous morphine deficiency plays a role in alcoholic addiction. The same biochemical patterns were obtained in those with right hemispheric chemical dominance. Alcoholic addiction, alcoholic cirrhosis, and acquired hepatocerebral degeneration occur in right hemispheric, chemically dominant individuals.

Topics: Adult; Alcoholism; Analysis of Variance; Cholesterol; Digoxin; Disease Susceptibility; Dolichols; Dominance, Cerebral; Enzyme Inhibitors; Erythrocytes; Female; Glycoconjugates; Glycosaminoglycans; Hepatolenticular Degeneration; Humans; Hydroxymethylglutaryl CoA Reductases; Hypothalamus; Liver Cirrhosis, Alcoholic; Male; Membrane Proteins; Neurotransmitter Agents; Polyisoprenyl Phosphates; Sodium-Potassium-Exchanging ATPase; Tryptophan; Tyrosine; Ubiquinone

Cerivastatine was administered as a reversible HMG-CoA reductase inhibitor (statine) to treat hypercholesterolemia until its withdrawal from the market following 52 reports of death due to drug-related rhabdomyolysis and acute renal failure. In most cases, cerivastatine was applied in combination with drugs which influenced the liver metabolism of cerivastatine via cytochromeoxidase P 450 isoenzymes. We report a well-documented case of acute rhabdomyolysis following cerivastatine monotherapy. The diagnosis was confirmed additionally by muscle biopsy.Finally,we give an overview of the current knowledge concerning therapy with HMG-CoA reductase inhibitors,1 year after the withdrawal of cerivastatine from the market.

Topics: Acute Disease; Anticholesteremic Agents; Aryl Hydrocarbon Hydroxylases; Biopsy; Coenzymes; Comorbidity; Creatine Kinase; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Diagnosis, Differential; Drug Interactions; Electromyography; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Liver Cirrhosis, Alcoholic; Liver Function Tests; Middle Aged; Muscle, Skeletal; Neurologic Examination; Pancreatic Diseases; Pyridines; Rhabdomyolysis; Stomach Neoplasms; Ubiquinone

Ubiquinone (CoQ10 coenzyme) is part of the respiratory chain in mitochondria, and acts as a scavenger in oxidative stress in cell membranes. Ubiquinone is mainly synthesized in the liver and partly derived from the diet; its plasma levels significantly correlate with tissue levels in experimental animals and in pathological states in man. By means of an original high-performance liquid chromatography technique, we measured ubiquinone plasma levels in 10 healthy subjects, in 27 patients with cirrhosis and in 22 chronic alcoholics with normal liver function. Ubiquinone levels were markedly reduced in cirrhosis (0.25 [SD 0.21] microgram/ml vs. 0.92 [0.38] in controls; P < 0.001), without any difference between alcohol- and non-alcohol-related disease. Also, in chronic alcoholics ubiquinone levels were nearly halved (0.49 [0.24]). In cirrhosis, ubiquinone plasma levels significantly correlated with cholesterol (P < 0.05), and with total bilirubin levels (P < 0.01). Our study highlights a remarkable deficiency in ubiquinone levels in patients with cirrhosis and in chronic alcoholics, to which both reduced hepatic synthesis and nutritional defects may contribute.

Topics: Alcoholism; Chromatography, High Pressure Liquid; Female; Humans; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Ubiquinone