Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute toxicity of individual PCBs, which were categorized as either phenobarbital (PB)- or 3-methylcholanthrene (MC)-type inducers, was examined in young male Wistar rats, comparing their effects on growth rate, organ weight and liver lipid content, 5 days after a single i.p. injection. PB-type PCBs (2,4,3',4'- and 2,5,2'5'-tetrachlorobiphenyl), which slightly increased a content of cytochrome P450, did not show any significant toxicity at a dose of 100 mg/kg. On the contrary, MC-type PCBs (3,4,5,3',4'-pentachloro- and 3,4,5,3',4',5'-hexachlorobiphenyl), which markedly increased a content of cytochrome P448, strongly reduced growth rate and weights of thymus and spleen at a dose of 10 mg/kg. Liver enlargement accompanied by fatty liver was also observed only with MC-type PCBs. 3,4,3',4'-Tetrachlorobiphenyl was also toxic at a dose of 50 mg/kg, in keeping with its weak MC-type-inducing ability. Pretreatment with MC affected neither growth rate, spleen weight, nor liver lipid content. These results suggest that the toxic potency of PCBs is related to their MC-type inducing ability, but the toxic characteristics are different from those of MC itself.
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PMID:Possible correlation between induction modes of hepatic enzymes by PCBs and their toxicity in rats. 11 Jan 91

We evaluated the effects of phenobarbital, an inducer, on plasma glucose and serum immunoreactive insulin levels and on hepatic glucose and drug metabolism using an animal model of non-insulin dependent diabetes mellitus. Genetically obese (ob/ob) mice, characterized by hyperglycaemia, hyperinsulinaemia, fatty liver and obesity were selected. The impairment of diabetic state with age was associated with increased activities of NADPH producing enzymes, whereas mixed function oxidase system remained unaltered. Phenobarbital reduced serum immunoreactive insulin and plasma glucose levels and decreased gluconeogenesis. Hepatic glucose phosphorylating enzyme activity increased and glucose releasing enzyme activity decreased. The demand for NADPH in drug oxidation reactions, caused by the induction phenomenon, was reflected in the elevated activities of the NADPH producing enzymes in pentose phosphate pathway and in the activities of isocitrate dehydrogenase and malic enzyme from mitochondrial oxidation reactions. Glucose metabolism of lean littermates indicated that phenobarbital induction normalizes impaired intracellular glucose handling but leaves normal glucose metabolism unaltered. Hepatic glucose production rate was related to plasma glucose, NADPH producing enzyme activities and cytochrome P450 content in the obese and lean mice.
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PMID:Effects of enzyme induction therapy on glucose and drug metabolism in obese mice model of non-insulin dependent diabetes mellitus. 250 Oct 61

Hydrazine hepatotoxicity in vivo, as manifested by triglyceride accumulation, depletion of ATP and reduced glutathione (GSH) was shown to be dose related. The effect of pretreatment of rats with various inhibitors and inducers of cytochrome P450 on these dose-response relationships was investigated. Pretreatment with the inhibitor piperonyl butoxide increased triglyceride accumulation whereas pretreatment with the inducers phenobarbital and beta-naphthoflavone (BNF) resulted in reduced triglyceride accumulation. Pretreatment with the inducers acetone and isoniazid also enhanced triglyceride accumulation. Only phenobarbital pretreatment also significantly reduced GSH and ATP depletion. A linear correlation was found between hepatic glutathione and ATP levels in non-pretreated animals given various doses of hydrazine. However, exponential relationships were found between hepatic triglycerides and both hepatic ATP and glutathione. The results suggest that i) the hepatotoxicity of hydrazine can be modulated by inducing or inhibiting particular isoenzymes of cytochrome P450, ii) ATP and GSH depletion may not be directly involved in the development of fatty liver.
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PMID:Influence of inducers and inhibitors of cytochrome P450 on the hepatotoxicity of hydrazine in vivo. 809 26

It is well established that chronic ethanol ingestion enhances lipid peroxidation in the liver in vivo and in vitro. The relationship of lipid peroxidation and protein adduct formation to morphologically assessed liver damage remains problematic. To help determine if a relationship exists between lipid peroxidation and liver pathology rats were fed ethanol and a high fat diet by continuous intragastric tube feeding for 72 days, maintaining the blood alcohol levels above 200 mg/dl. This model induced a fatty liver with focal necrosis and fibrosis. This pathology was associated with an increased total cytochrome P450, an increased cytochrome P450 2E1 isoenzyme (CYP2E1), a decrease in the NADPH-cytochrome P450 reductase activity, an increased rate of NADPH oxidation and an increased NADPH-dependent lipid peroxidation in liver microsomes compared to controls. Serum protein adducts with malondialdehyde 4-hydroxynonenal were significantly increased. Thus, the alcohol-induced liver pathology was associated with the induction of CYP2EI, lipid peroxidation, and protein adduct formation. When isoniazid (INH) in therapeutic doses was fed to rats with ethanol these parameters were changed in that central-central bridging fibrosis was increased, as was lipid peroxidation, whereas INH reduced the ethanol-induced decrease in the reductase, the increase in total P450 and CYP2EI, as well as the NADPH oxidation rate and the elevation of serum transaminase levels. The results tend to link central-central bridging fibrosis with increased lipid peroxidation and aldehyde-protein adduct formation caused by ethanol.
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PMID:Effect of ethanol on cytochrome P450 2E1 (CYP2E1), lipid peroxidation, and serum protein adduct formation in relation to liver pathology pathogenesis. 845 37

Alcohol-induced tissue damage results from associated nutritional deficiencies as well as some direct toxic effects, which have now been linked to the metabolism of ethanol. The main pathway involves liver alcohol dehydrogenase which catalyzes the oxidation of ethanol to acetaldehyde, with a shift to a more reduced state, and results in metabolic disturbances, such as hyperlactacidemia, acidosis, hyperglycemia, hyperuricemia and fatty liver. More severe toxic manifestations are produced by an accessory pathway, the microsomal ethanol oxidizing system involving an ethanol-inducible cytochrome P450 (2E1). After chronic ethanol consumption, there is a 4- to 10-fold induction of 2E1, associated not only with increased acetaldehyde generation but also with production of oxygen radicals that promote lipid peroxidation. Most importantly, 2E1 activates many xenobiotics to toxic metabolites. These include solvents commonly used in industry, anaesthetic agents, medications such as isoniazid, over the counter analgesics (acetaminophen), illicit drugs (cocaine), chemical carcinogens, and even vitamin A and its precursor beta-carotene. Furthermore, enhanced microsomal degradation of retinoids (together with increased hepatic mobilization) promotes their depletion and associated pathology. Induction of 2E1 also yields increased acetaldehyde generation, with formation of protein adducts, resulting in antibody production, enzyme inactivation, decreased DNA repair, impaired utilization of oxygen, glutathione depletion, free radical-mediated toxicity, lipid peroxidation, and increased collagen synthesis. New therapies include adenosyl-L-methionine which, in baboons, replenishes glutathione, and attenuates mitochondrial lesions. In addition, polyenylphosphatidylcholine (PPC) fully prevents ethanol-induced septal fibrosis and cirrhosis, opposes ethanol-induced hepatic phospholipid depletion, decreased phosphatidylethanolamine methyltransferase activity and activation of hepatic lipocytes, whereas its dilinoleoyl species increases collagenase activity. Current clinical trials with PPC are targeted on susceptible populations, namely heavy drinkers at precirrhotic stages.
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PMID:Ethanol metabolism, cirrhosis and alcoholism. 902 26

We hypothesized that the lipid-activated transcription factor, the peroxisome proliferator-activated receptor alpha (PPARalpha), plays a pivotal role in the cellular metabolic response to fasting. Short-term starvation caused hepatic steatosis, myocardial lipid accumulation, and hypoglycemia, with an inadequate ketogenic response in adult mice lacking PPARalpha (PPARalpha-/-), a phenotype that bears remarkable similarity to that of humans with genetic defects in mitochondrial fatty acid oxidation enzymes. In PPARalpha+/+ mice, fasting induced the hepatic and cardiac expression of PPARalpha target genes encoding key mitochondrial (medium-chain acyl-CoA dehydrogenase, carnitine palmitoyltransferase I) and extramitochondrial (acyl-CoA oxidase, cytochrome P450 4A3) enzymes. In striking contrast, the hepatic and cardiac expression of most PPARalpha target genes was not induced by fasting in PPARalpha-/- mice. These results define a critical role for PPARalpha in a transcriptional regulatory response to fasting and identify the PPARalpha-/- mouse as a potentially useful murine model of inborn and acquired abnormalities of human fatty acid utilization.
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PMID:A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders. 1037 39

Fatty acid beta-oxidation occurs in both mitochondria and peroxisomes. Long chain fatty acids are also metabolized by the cytochrome P450 CYP4A omega-oxidation enzymes to toxic dicarboxylic acids (DCAs) that serve as substrates for peroxisomal beta-oxidation. Synthetic peroxisome proliferators interact with peroxisome proliferator activated receptor alpha (PPARalpha) to transcriptionally activate genes that participate in peroxisomal, microsomal, and mitochondrial fatty acid oxidation. Mice lacking PPARalpha (PPARalpha-/-) fail to respond to the inductive effects of peroxisome proliferators, whereas those lacking fatty acyl-CoA oxidase (AOX-/-), the first enzyme of the peroxisomal beta-oxidation system, exhibit extensive microvesicular steatohepatitis, leading to hepatocellular regeneration and massive peroxisome proliferation, implying sustained activation of PPARalpha by natural ligands. We now report that mice nullizygous for both PPARalpha and AOX (PPARalpha-/- AOX-/-) failed to exhibit spontaneous peroxisome proliferation and induction of PPARalpha-regulated genes by biological ligands unmetabolized in the absence of AOX. In AOX-/- mice, the hyperactivity of PPARalpha enhances the severity of steatosis by inducing CYP4A family proteins that generate DCAs and since they are not metabolized in the absence of peroxisomal beta-oxidation, they damage mitochondria leading to steatosis. Blunting of microvesicular steatosis, which is restricted to few liver cells in periportal regions in PPARalpha-/- AOX-/- mice, suggests a role for PPARalpha-induced genes, especially members of CYP4A family, in determining the severity of steatosis in livers with defective peroxisomal beta-oxidation. In age-matched PPARalpha-/- mice, a decrease in constitutive mitochondrial beta-oxidation with intact constitutive peroxisomal beta-oxidation system contributes to large droplet fatty change that is restricted to centrilobular hepatocytes. These data define a critical role for both PPARalpha and AOX in hepatic lipid metabolism and in the pathogenesis of specific fatty liver phenotype.
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PMID:Peroxisomal and mitochondrial fatty acid beta-oxidation in mice nullizygous for both peroxisome proliferator-activated receptor alpha and peroxisomal fatty acyl-CoA oxidase. Genotype correlation with fatty liver phenotype. 1038 30

Alcohol (ethanol) was administered chronically to female Sprague-Dawley rats in a nutritionally adequate, totally liquid diet for 28 days. This resulted in significant hepatic steatosis and lipid peroxidation. When taurine was administered for 2 days following alcohol withdrawal it was found to reduce alcohol-induced lipid peroxidation and completely reversed hepatic steatosis. The reversal of hepatic steatosis was demonstrated both biochemically and histologically. Two days following alcohol withdrawal, the apparent activity of the alcohol-inducible form of cytochrome P450 (CYP2E1) was unchanged although total cytochrome P450 content was increased. In addition, alcohol significantly inhibited hepatic methionine synthase activity and increased homocysteine excretion in urine. Although alcohol did not affect the urinary excretion of taurine (a non-invasive marker of liver damage), levels of serum and hepatic taurine were markedly raised in animals given taurine following their treatment with alcohol, compared to animals given taurine alone. There was evidence of slight bile duct injury in animals treated with alcohol and with alcohol followed by taurine, as indicated by raised serum alkaline phosphatase (ALP) and cholesterol. Aspartate aminotransferase (AST) was also slightly raised. The effects of taurine on reversing hepatic steatosis may be due to the enhanced secretion of hepatic triglycerides. It is suggested that increased bile flow as a result of taurine treatment may have contributed to the removal of lipid peroxides. These in-vivo findings demonstrate for the first time that hepatic steatosis and lipid peroxidation, occurring as a result of chronic alcohol consumption, can be reversed by administration of taurine to rats for 2 days.
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PMID:Reversal of ethanol-induced hepatic steatosis and lipid peroxidation by taurine: a study in rats. 1078 1

The ethanol inducible isoform of cytochrome P450, CYP2E1, may play a role in ethanol-induced liver injury. Therefore, the factors which govern CYP2E1 degradation and turnover were investigated. These factors include cAMP, ubiquitin, proteasomal enzymes and CYP2E1 mRNA. Rats fed ethanol or pair-fed isocaloric dextrose were pair-fed with rats fed ethanol or dextrose treated with cAMP for 2 months. The liver pathology, regenerative activity, fatty acid composition, NFkappaB activation, ubiquitin conjugates and proteasomal enzymes were measured as were the apoprotein levels of CYP2E1, CYP3A, CYP4A and mRNA levels for CYP2E1 and ubiquitin expression. The results showed, that the cAMP treatment ameliorated the increase liver fat storage and changes in the fatty acid composition in the livers of ethanol fed rats. Other histologic features of alcoholic liver disease were not changed. Western blot quantitation showed that the amount of ubiquitin and ubiquitin conjugates were markedly reduced by ethanol treatment. Similarly, ethanol decreased the level of ubiquitin mRNA. cAMP ameliorated the inhibition of the proteasomal enzyme proteolysis caused by ethanol feeding. The ethanol-induced increase in the CYP2E1 protein was partially inhibited by cAMP treatment. cAMP treatment decreased CYP2E1 mRNA levels in both ethanol-fed and pair fed control rats. Likewise NFkappaB activation was not increased by ethanol but cAMP reduced the level of NFkappaB activation. CAMP treatment also reduced CYP4A but not CYP3A. The results support the concept that cAMP treatment partially protects the liver from ethanol-induced fatty liver by reducing CYP2E1 induction through cAMP's effects on CYP2E1 synthesis.
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PMID:Role of CYP2E1 in the pathogenesis of alcoholic liver disease: modifications by cAMP and ubiquitin-proteasome pathway. 1047 71

Dietary habits are often considered as a pathogenic factor for fatty liver. The impact of dietary intake and steatosis on drug metabolism remains poorly investigated. Our aim was to assess the effect of dietary intake on in vivo cytochrome P450 (CYP) activities in eleven patients with abnormal liver function tests potentially due to fatty liver and associated with a high-sugar diet. Liver function tests, liver volume, aminopyrine breath test (ABT) and chlorzoxazone (CZ) pharmacokinetics (area under the curve, AUC) which are known to reflect CYP2E1 activity were evaluated before and after 2 months restriction of dietary sugar intake. Features at inclusion were an increased BMI (30.3 (SD 3.2) kg/m2), high hepatic volume (1.96 (SD 0.48) litres), hyperechogenic liver parenchyma, elevated liver enzyme activities (alanine aminotransferase (EC 2.6.1.2) 58.6 (SD 17.4) IU/1 with alanine aminotransferase: aspartate aminotransferase (EC 2.6.1.1) ratio > 1), together with a normal ABT value (0.68 (SD 0.21)% specific activity of administered dose of [14C]aminopyrine in breath after 1 h) and a high CYP2E1 activity (CZ AUC 20.3 (SD 7.1) micrograms/ml per h). A dietary sugar restriction was prescribed. On the basis of repeated interviews by the same dietitian, unaware of any clinical and biochemical data, six patients remained complaint to the diet and exhibited reductions in BMI (P < 0.001), serum alanine aminotransferase (P = 0.008), liver volume (P = 0.002) and CYP2E1 activity (P = 0.007), a significant increase in ABT (P < 0.001) together with the disappearance of liver hyperechogenicity at ultrasound. In contrast, the five non-compliant patients did not show any significant change in any of these variables. In conclusion, CYP2E1 activity is induced in patients with perturbations of liver function tests potentially due to fatty liver. In these patients, effective dietary sugar restriction is associated with a reduction in liver volume, a reduction in CYP2E1 activity and an increased aminopyrine metabolism rate.
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PMID:Dietary restriction of energy and sugar results in a reduction in human cytochrome P450 2E1 activity. 1065 74


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