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Relation of NAT2, CYP2E1 and GST Gene Polymorphisms with Anti-tuberculosis Treatment Induced Hepatotoxicity in North Indian Patients
Abstracts
HEPATOTOXICITY Effect of Different Doses of Wheatgrass in Prevention of Carbon Tetrachloride Induced Hepatotoxicity in Rats JK Kamboj*, SV Rana*, DK Dhawan**, K Vahiphei*** Departments of *Gastroenterology and **Pathology, PGIMER, Chandigarh, ***Department of Biophysics, Punjab University, Chandigarh Introduction: Wheatgrass (Triticum aestivum), rich in chlorophyll and various antioxidants, is promoted to treat a number of conditions including common cold, cough, fever, eczema and burns, etc. Aim: To determine the protective effect of different doses of wheatgrass in hepatic tissue of Wistar rats damaged by CCl4. Material and Methods: Wheatgrass was administered orally at different doses of 20 mg, 40 mg, 60 mg and 80 mg/100 g by body weight in drinking water for 4 weeks along with CCl4 injection given subcutaneously at a dose of 2 mL/Kg body weight twice a week. Wheatgrass dose was started 2 weeks prior to first injection of CCl4. Carbon tetrachloride was also administered in control group for 4 weeks and one group was given only wheatgrass at a maximum dose of 80 mg/100 g by body weight/day to check any adverse effect of wheatgrass on liver. The effect to different treatments was studied on serum enzymes like alkaline phosphatase (ALP), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in rats at different time intervals of 2 and 4 weeks and the rat liver was analyzed histologically at the end of study. Results: Serum ALP, AST, ALT activity was significantly increased when estimated at the intervals of 2 and 4 weeks as compared to baseline values in CCl4 group. Interestingly, supplementation of wheatgrass to rats helped in regulating the altered activities of ALP, AST and ALT in serum at 4 weeks. However, wheatgrass treatment to rats did not indicate any significant change in the activities of all abovementioned liver enzymes at the interval of 2 weeks. Histologically, there was necrosis, portal triaditis and lobular inflammation in CCl4 group. Maximum protection was observed biochemically and histologically with wheatgrass dose of 80 mg/100 g body weight Conclusion: Carbon tetrachloride caused liver toxicity and wheatgrass treatment prevented the increase in liver enzymes and histology depending on the dose of wheatgrass. Conflict of Interest: None
Relation of NAT2, CYP2E1 and GST Gene Polymorphisms with Anti-tuberculosis Treatment Induced Hepatotoxicity in North Indian Patients SV Rana*, SK Sharma**, RP Ola*, SK Arora***, SK Sinha*, JK Kamboj*, K Singh* Department of Superspecialty of *Gastroenterology, **Biophysics and ***Immunopathology, PGIMER, Chandigarh Background: Antituberculosis treatment (ATT) induced hepatitis is attributed to isoniazid (INH). Isoniazid is metabolized by hepatic N-acetyltransferase-2 (NAT-2) and cytochrome P-450 2E1 (CYP2E1) to form hepatotoxins. Glutathione-S-transferase (GST) plays an important role in prevention of ATT-induced hepatotoxicity. Deficiency of GST activity because of homozygous null mutations at GSTM1 and GSTT1 loci may modulate susceptibility to ATT-induced hepatotoxicity. Aim: To evaluate whether polymorphisms of NAT-2, GST and CYP2E1 gene were associated with ATT-induced hepatotoxicity in North Indian patients. Methods: In this prospective study, 250 patients treated with ATT for tuberculosis were genotyped for polymorphisms of NAT-2, GST and CYP2E1. NAT-2, CYP2E1 and GST genotypes were determined by PCR and multiplex PCR with restriction fragment length polymorphism analysis (RFLP). Results: Two hundred fifty tuberculosis (TB) patients on ATT (153 males) were studied. Out of 250 patients, 32 (12.8%) developed hepatotoxicity. NAT-2 gene allele 4/4 was present in 18/32 (56.2%) of hepatotoxicity patients while in 76/218 (34.8%) in non-hepatotoxicity patients. Allele 4/6, 5/5, 6/6 and 7/7 were not present in hepatotoxicity patients while these were present in non-hepatotoxicity patients. In GST, out of 32 hepatotoxicity patients, 5 (15.6%) showed GSTM1, 9 out of 32 (28.0%) GSTT1 and 18 out of 32 (56.3%) GSTT1/ GSTM1/ß-globulin. While 69 out of 218 (31.7%) showed GSTM1, 34 (15.6%) GSTT1, and 115 (52.7%) GSTT1/GSTM1/ß-globulin in nonhepatotoxicity patients. For CYP2E1 c1/c1, c2/c2 and c1/c2 genotypes in INH-NH patients were 61.1%, 16.6% and 22.2% respectively while in INH-H patients 50.0%, 25.0% and 25.0% respectively. Conclusion: This study suggests that NAT-2 gene allele 4/4 was significantly higher in INH-induced hepatotoxicity as compared to nonhepatotoxicity group. There was no significant difference in CYP2E1 and GST genotypes between both the groups. Conflict of Interest: None
© 2011, INASL
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HEPATOTOXICITY Effect of Different Doses of Wheatgrass in Prevention of Carbon Tetrachloride Induced Hepatotoxicity in Rats JK Kamboj*, SV Rana*, DK Dhawan**, K Vahiphei*** Departments of *Gastroenterology and **Pathology, PGIMER, Chandigarh, ***Department of Biophysics, Punjab University, Chandigarh Introduction: Wheatgrass (Triticum aestivum), rich in chlorophyll and various antioxidants, is promoted to treat a number of conditions including common cold, cough, fever, eczema and burns, etc. Aim: To determine the protective effect of different doses of wheatgrass in hepatic tissue of Wistar rats damaged by CCl4. Material and Methods: Wheatgrass was administered orally at different doses of 20 mg, 40 mg, 60 mg and 80 mg/100 g by body weight in drinking water for 4 weeks along with CCl4 injection given subcutaneously at a dose of 2 mL/Kg body weight twice a week. Wheatgrass dose was started 2 weeks prior to first injection of CCl4. Carbon tetrachloride was also administered in control group for 4 weeks and one group was given only wheatgrass at a maximum dose of 80 mg/100 g by body weight/day to check any adverse effect of wheatgrass on liver. The effect to different treatments was studied on serum enzymes like alkaline phosphatase (ALP), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in rats at different time intervals of 2 and 4 weeks and the rat liver was analyzed histologically at the end of study. Results: Serum ALP, AST, ALT activity was significantly increased when estimated at the intervals of 2 and 4 weeks as compared to baseline values in CCl4 group. Interestingly, supplementation of wheatgrass to rats helped in regulating the altered activities of ALP, AST and ALT in serum at 4 weeks. However, wheatgrass treatment to rats did not indicate any significant change in the activities of all abovementioned liver enzymes at the interval of 2 weeks. Histologically, there was necrosis, portal triaditis and lobular inflammation in CCl4 group. Maximum protection was observed biochemically and histologically with wheatgrass dose of 80 mg/100 g body weight Conclusion: Carbon tetrachloride caused liver toxicity and wheatgrass treatment prevented the increase in liver enzymes and histology depending on the dose of wheatgrass. Conflict of Interest: None
Relation of NAT2, CYP2E1 and GST Gene Polymorphisms with Anti-tuberculosis Treatment Induced Hepatotoxicity in North Indian Patients SV Rana*, SK Sharma**, RP Ola*, SK Arora***, SK Sinha*, JK Kamboj*, K Singh* Department of Superspecialty of *Gastroenterology, **Biophysics and ***Immunopathology, PGIMER, Chandigarh Background: Antituberculosis treatment (ATT) induced hepatitis is attributed to isoniazid (INH). Isoniazid is metabolized by hepatic N-acetyltransferase-2 (NAT-2) and cytochrome P-450 2E1 (CYP2E1) to form hepatotoxins. Glutathione-S-transferase (GST) plays an important role in prevention of ATT-induced hepatotoxicity. Deficiency of GST activity because of homozygous null mutations at GSTM1 and GSTT1 loci may modulate susceptibility to ATT-induced hepatotoxicity. Aim: To evaluate whether polymorphisms of NAT-2, GST and CYP2E1 gene were associated with ATT-induced hepatotoxicity in North Indian patients. Methods: In this prospective study, 250 patients treated with ATT for tuberculosis were genotyped for polymorphisms of NAT-2, GST and CYP2E1. NAT-2, CYP2E1 and GST genotypes were determined by PCR and multiplex PCR with restriction fragment length polymorphism analysis (RFLP). Results: Two hundred fifty tuberculosis (TB) patients on ATT (153 males) were studied. Out of 250 patients, 32 (12.8%) developed hepatotoxicity. NAT-2 gene allele 4/4 was present in 18/32 (56.2%) of hepatotoxicity patients while in 76/218 (34.8%) in non-hepatotoxicity patients. Allele 4/6, 5/5, 6/6 and 7/7 were not present in hepatotoxicity patients while these were present in non-hepatotoxicity patients. In GST, out of 32 hepatotoxicity patients, 5 (15.6%) showed GSTM1, 9 out of 32 (28.0%) GSTT1 and 18 out of 32 (56.3%) GSTT1/ GSTM1/ß-globulin. While 69 out of 218 (31.7%) showed GSTM1, 34 (15.6%) GSTT1, and 115 (52.7%) GSTT1/GSTM1/ß-globulin in nonhepatotoxicity patients. For CYP2E1 c1/c1, c2/c2 and c1/c2 genotypes in INH-NH patients were 61.1%, 16.6% and 22.2% respectively while in INH-H patients 50.0%, 25.0% and 25.0% respectively. Conclusion: This study suggests that NAT-2 gene allele 4/4 was significantly higher in INH-induced hepatotoxicity as compared to nonhepatotoxicity group. There was no significant difference in CYP2E1 and GST genotypes between both the groups. Conflict of Interest: None
© 2011, INASL
39