Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated glutathione S-transferase (GST) P1 Ile (105) Val, T1, and M1 polymorphisms in 45 patients with documented cryptogenic cirrhosis and 56 healthy control subjects. Polymerase chain reaction-based procedures were performed in the studied populations to confirm the genotypes of GSTT1, M1, and P1. Ile/Val and Val/Val GSTP1 genotypes were more frequent in the patients with cirrhosis (n=39, 87%) than in the control subjects (n=10; 18%) (odds ratio [OR] 34.04; 95% confidence interval [CI] 10.70 to 108.31, P<0.001). Among these patients with cirrhosis, 16 were heterozygous and 23 were homozygous, whereas only one person in the control group was homozygous. The GSTM1 null genotype was also more prevalent in cirrhotic patients than in healthy control subjects (OR 6.83, 95% CI 2.53 to 18.42, P<0.001). The rate of GSTT1 deletion did not show a significant difference between the two groups (OR 2.35, 95% CI 0.76 to 7.28, P=0.111). To our knowledge, this is the first evidence that GSTP1 and GSTM1 polymorphisms may be related to the development of cirrhosis by unknown mechanisms. The significant association of cryptogenic cirrhosis with Val/Val GSTP1 genotype encoding a low detoxification activity protein implicates this polymorphism as a risk factor for the occurrence of the disease.
 ...
PMID:GSTP1, GSTM1, and GSTT1 genetic polymorphisms in patients with cryptogenic liver cirrhosis. 1512 Mar 66

Excessive alcohol consumption may cause the development of pathologies in the liver and pancreas and various digestive tract cancers. The enzymes GSTM1, GSTT1, GSTP1, CYP1A1 and CYP2E1 are involved in the bioactivation and detoxification of a variety of xenobiotics present in food, organic solvents, tobacco smoke, drugs, pesticides, environmental pollutants and alcoholic drinks. Polymorphisms in the genes coding for these enzymes have been associated with susceptibility to different diseases, including ethanol-related diseases. To investigate whether these polymorphisms represent risk-modifying factors for ethanol-related diseases, a study was conducted involving 120 Brazilian alcoholics and 221 controls with similar ethnic backgrounds. The distribution of alcoholics groups was as follows: 65 with liver cirrhosis, 14 with chronic pancreatitis and 41 without cirrhosis or pancreatitis. The data revealed that carriers of the rare GSTP1 Val allele were at higher risk of liver cirrhosis and pancreatitis, since we found higher frequencies of the Val/Val genotype in alcoholics with liver cirrhosis (15.4%) and pancreatitis (28.6%) in comparison with alcoholics without disease (7.3%). No differences were found in the prevalences of the GSTM1 and GSTT1 null genotypes between alcoholics and the controls and no association was found between the rare CYP2E1 c2 allele and liver cirrhosis and pancreatitis. However, when the mutant CYP1A1 allele was compared between alcoholics and controls, the m2/m2 genotype was more prevalent in the liver cirrhosis alcoholics (7.7%) than in the controls (1.4%) and this difference was statistically significant (P = 0.03, OR = 5.33). In conclusion, our data indicate an association between occurrence of the Val/Val GSTP1 genotype and chronic pancreatitis and an association between the m2/m2 CYP1A1 genotype and alcoholic liver cirrhosis. This could indicate that persons with these genotypes are genetically more prone to the development of alcoholic pancreatitis and alcoholic cirrhosis, respectively.
 ...
PMID:Polymorphisms in glutathione S-transferases GSTM1, GSTT1 and GSTP1 and cytochromes P450 CYP2E1 and CYP1A1 and susceptibility to cirrhosis or pancreatitis in alcoholics. 1521 28

Apart from infectious or viral hepatitis, other most common non-infectious causes of hepatitis are alcohol, cholestatic, drugs and toxic materials. The most common mode that leads to liver injuries is antituberculosis drug-induced hepatitis. The severity of drug-induced liver injury varies from minor nonspecific changes in hepatic structure to fulminant hepatic failure, cirrhosis and liver cancer. Patients receiving antitubercular drug frequently develop acute or chronic hepatitis. The time required for the metabolites to reach hepatotoxic levels is much earlier with isoniazid plus rifampicin treatment than isoniazid alone and this has been shown to be synergistic rather than additive. Antituberculosis drug (ATT)-inducible cytochrome P-4502E1 (CYP2E1) is constitutively expressed in the liver. Recent studies show that polymorphism of the N-acetyltransferase 2 (NAT2) genes and glutathione-S-transferase (GST) are the major susceptibility risk factors for ATT-induced hepatitis. The hepatic NAT and GST are involved in the metabolism of several carcinogenic arylamines and drugs. The NAT2 enzyme has a genetic polymorphism in human. N-acetyltransferase 2 genes (NAT2) have been identified to be responsible for genetic polymorphism of slow and rapid acetylation in humans. Slow acetylators of NAT2 prove to develop more severe hepatotoxicity than rapid acetylators making it a significant risk factor. Deficiency of GST activity, because of homozygous null mutations at GSTM1 and GSTT1 loci, may modulate susceptibility to drug and xenobiotic-induced hepatotoxicity. Polymorphisms at GSTM1, GSTT1 and NAT2 loci had been linked to various forms of liver injury, including hepatocellular carcinoma.
 ...
PMID:Antituberculosis drug-induced hepatitis: risk factors, prevention and management. 1533 88

Although a relationship between vinyl chloride monomer (VCM) and liver cirrhosis has been reported, the underlying mechanisms are not clear. Cytochrome P450 2E1 (CYP2E1), aldehyde dehydrogenase 2 (ALDH2) and glutathione S-transferase theta 1 (GSTT1) enzymes are involved in activation and detoxification of VCM, and thus may be important determinants of interindividual susceptibility to VCM-induced liver damage, including liver cirrhosis. The objective of this study was to evaluate if metabolizing genetic polymorphisms could modify individual susceptibility to liver fibrosis of the VCM exposure. CYP2E1, ALDH2, and GSTT1 polymorphisms were determined by the PCR-RFLP method among 320 workers who were employed in five polyvinyl chloride manufacturing plants. Cumulative VCM exposure levels for study subjects were calculated using a job exposure matrix model. Thirteen workers were diagnosed as having liver fibrosis by using ultrasonography. We observed a dose-response trend between VCM exposure and liver fibrosis. Regarding the results on genetic polymorphisms, CYP2E1 c2c2 genotype showed a significant increase in the risk of liver fibrosis as compared to those with CYP2E1 c1c1 or c1c2 genotypes. No differences were observed between GSTT1 and ALDH2 genotypes and liver fibrosis. In summary, our result suggests that genetic polymorphism in CYP2E1 may be responsible for individual differences in susceptibility to liver fibrosis with regard to chronic VCM exposure. Thus, polymorphism analysis of metabolizing enzymes might be useful in the risk assessment of liver damage in workers with VCM exposure.
 ...
PMID:Effect of the CYP2E1 genotype on vinyl chloride monomer-induced liver fibrosis among polyvinyl chloride workers. 1765 24

Genetic polymorphic forms of glutathione-S-transferase (GST) were found to be associated with risk for various malignancies. The present study was undertaken to evaluate the risks-associated with GSTT1 and GSTM1 gene polymorphisms and hepatitis virus-related hepatocellular carcinoma (HCC) in an Egyptian population. Sixty patients diagnosed with HCC were subdivided into 3 groups: group I, 31 patients with HCC and HCV-related cirrhosis; group II, 19 patients with HCC and HBV- related cirrhosis and group III, 10 patients with HCC and cirrhosis of non-viral aetiology. Fifty cirrhotic patients without HCC were also included as a control group. Patients and controls were subjected to thorough history taking and clinical examination, liver function tests, hepatitis viral markers, anti-Bilharzial antibodies and serum alpha fetoprotein levels. Rectal snip for the diagnosis of active Bilharziasis, abdominal ultra-sonography and CT abdomen were performed for patients as well as liver biopsy when indicated. GSTM1 and GSTT1 were tested in peripheral blood mononuclear cells by PCR. GSTM1 gene deletion (null genotype) was observed in 56.7% of HCC patients and in 38% of the control group (P < 0.05). The GSTT1 null genotype was detected in 41.7% of the HCC patients compared to 22% of control patients (P < 0.05). The double genes null of GSTM1 and GSTT1 was detected in 10% of all HCC patients and in 2% of the control cases (P < 0.05). Comparison between the subgroups of HCC revealed that the GSTM1 null genotype was detected in 67.7% of group I, 47.4% of group II and 40% of group III cases, with a significant increase in group I compared to other HCC subgroups (P < 0.001). In addition, the GSTT1 null gene was observed in 35.5% of group I, 57.9% of group II, and 30% of group III, with a significant increase in group II (P < 0.01). In conclusion, our findings suggest that GSTM1 and GSTT1 polymorphisms appear to be associated with a modest increase in the risk of HCC in Egyptian patients. Studies with a larger sample size are still required to confirm the results and to explore the association with risk factors other than HCV and HBV in this population.
 ...
PMID:Gene deletion of glutathione S-transferase M1 and T1 and risk factors of hepatocellular carcinoma in Egyptian patients. 2030 95

Association of deletion polymorphism in GSTT1 and GSTM1 genes and polymorphic variant A313G of GSTP1 gene with cirrhosis diseases and 4-year survival rate for the Tomsk region (West Siberia) patients were tested. Homozygous deletion of GSTM1 gene (null genotype) was a protective factor for alcoholic and mixed (HCV, HBV and alcohol) liver cirrhosis development. The patients from the joint group (all etiology forms) as well as having alcoholic and mixed cirrhosis had lower frequency of GSTM1 null genotype (39.2, 39.0, and 34.2%, respectively) in comparison with the control group (64.6%). The GSTM1 null genotype and GSTP1 gene A313G polymorphic variant correlated with the patients' survival rate. The patients survived in comparison with the dead had higher frequency of a GSTM1 null genotype (46.6 vs. 30.2%) and GSTP1 AA genotype (63.1 vs. 40.5%), and lower frequency of GSTP1 AG (A313G) genotype (31.1 vs. 51.2%). A survival rate was 2.5 times higher for patients having GSTP1 AA genotype in comparison with the GG and AG genotype carriers and 2 times higher for patients having GSTM1 null genotype than the gene carriers. A 4-year fatal case probability was 2.3 times higher among the patients having heterozygous AG GSTP1 genotype in comparison with homozygous AA and GG genotype carriers.
 ...
PMID:[Liver cirrhosis patogenetics: polymorphism of glutation S-transferase genes]. 2060 66

The glutathione S-transferase (GST) supergene family is made up of four gene families responsible for the biotransformation of drugs and other xenobiotics. Genetic variations in this supergene family influence individual detoxification levels and may contribute to the development of cancer. A hospital-based case-control study was conducted to evaluate the association between GST polymorphism among Filipino patients positive for hepatitis B virus (HBV DNA) and clinically diagnosed as either with chronic active hepatitis, liver cirrhosis, and hepatocellular carcinoma as well as normal individuals negative for HBV infection. Multiplex PCR was used to detect the presence or absence of the GSTT1 and GSTM1 polymorphisms in peripheral blood. DNA sequencing of the S gene region of the virus was used to determine the predominant genotype found among HBV-infected patients. Our results showed that the odds of having a chronic liver disease is only 0.95 (95% CI 0.58-1.57) among those with GSTT1 null genotype compared to those with GSTT1+ genotype. On the other hand, the odds of chronic liver disease is 17.85 times (95% CI 7.34-43.45) for those with GSTM1 null genotype compared to those with GSTM1+ genotype. Using the GSTT1+/GSTM1+ genotype as the reference, both GSTT1+/GSTM1- (OR 16.61; 95% CI 6.69-41.22) and GSTT1-/GSTM1- (OR 11.91; 95% CI 4.48-31.66) genotypes seem to be risk factors for chronic liver disease. From our observations, we conclude that polymorphism in GSTM1 null genotype (OR 17.85; 95% CI 7.34-43.45) seem to be associated with an increased risk of chronic liver disease among Filipinos.
 ...
PMID:Association of glutathione S-transferase T1 and M1 genotypes with chronic liver diseases among Filipinos. 2272 52

Chronic alcohol and tobacco abuse plays a crucial role in the development of different liver associated disorders. Intake promotes the generation of reactive oxygen species within hepatic cells exposing their DNA to continuous oxidative stress which finally leads to DNA damage. However in response to such damage an entangled protective repair machinery comprising different repair proteins like ATM, ATR, H2AX, MRN complex becomes activated. Under abnormal conditions the excessive reactive oxygen species generation results in genetic predisposition of various genes (as ADH, ALDH, CYP2E1, GSTT1, GSTP1 and GSTM1) involved in xenobiotic metabolic pathways, associated with susceptibility to different liver related diseases such as fibrosis, cirrhosis and hepatocellular carcinoma. There is increasing evidence that the inflammatory process is inherently associated with many different cancer types, including hepatocellular carcinomas. The generated reactive oxygen species can also activate or repress epigenetic elements such as chromatin remodeling, non-coding RNAs (micro-RNAs), DNA (de) methylation and histone modification that affect gene expression, hence leading to various disorders. The present review provides comprehensive knowledge of different molecular mechanisms involved in gene polymorphism and their possible association with alcohol and tobacco consumption. The article also showcases the necessity of identifying novel diagnostic biomarkers for early cancer risk assessment among alcohol and tobacco users.
...
PMID:Molecular Links between Alcohol and Tobacco Induced DNA Damage, Gene Polymorphisms and Patho-physiological Consequences: A Systematic Review of Hepatic Carcinogenesis. 2616 95