Skip to main content
Top
Published in: BMC Neurology 1/2018

Open Access 01-12-2018 | Research article

Glutathione S-transferase M1 and T1 polymorphisms and the risk of mild hepatotoxicity induced by carbamazepine in a tunisian population study

Authors: Chahra Chbili, Anis Hassine, Neila Fathallah, Manel Nouira, Salma Naija, Sofiene Ben Ammou, Saad Saguem

Published in: BMC Neurology | Issue 1/2018

Login to get access

Abstract

Background

The aim of this study was to evaluate whether the glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) null alleles may contribute to carbamazepine-induced hepatotoxicity.

Methods

A cross-sectional prospective study was conducted to identify the frequency distribution of GSTM1 and GSTT1 alleles in 129 Tunisian epileptic patients treated with carbamazepine. Null alleles were determined using a Polymerase Chain Reaction. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured by standard methods.

Results

Our results showed that the frequencies of GSTM1 (−) null allele and GSTT1 null (−) allele were 74.4 and 17.8% respectively. The ALT and AST levels were elevated in 46 (35.7%) and 33 (25.6%) cases. The mean values of ALT and AST were approximately 1.32 and 3.61 times higher than the upper limit of normal levels, respectively. The values of ALT and AST were significantly higher in GSTM1 (−) allele than in GSTM1 (+) (p = 10−3.and 0.004, respectively).
The level of ALT was significantly higher in combination of GSTM1 (−)/T1(−) than in combined GSTM1(−)/T1(+) and combined GSTM1(+)/T1(+) (p = 0.2 and 0.03, respectively), and that of AST was significantly higher in combination of GSTM1(−)/T1(−) and in combination of GSTM1(+)/T1(−) than in combination of GSTM1(+)/T1(+) (p = 10−3 and 10−3, respectively).

Conclusions

Our findings suggest that the GSTM1 (−) allele may be considered as a key factor for the development of carbamazepine-induced hepatotoxicity. Results related to GSTT (−) allele and elevation in AST levels should be considered with caution as AST may be elevated in other pathophysiological conditions.
Literature
1.
go back to reference Ek O, Ban E, Woo JS, Kim CK. Analysis of carbamazepine and its active metabolite, carbamazepine-10,11-epoxide, in human plasma using high-performance liquid chromatography. Anal Bioanal Chem. 2006;386(6):1931–6.CrossRef Ek O, Ban E, Woo JS, Kim CK. Analysis of carbamazepine and its active metabolite, carbamazepine-10,11-epoxide, in human plasma using high-performance liquid chromatography. Anal Bioanal Chem. 2006;386(6):1931–6.CrossRef
3.
go back to reference Kalapos MP. Carbamazepine-provoked hepatotoxicity and possible aetiopathological role of glutathione in the events. Retrospective review of old data and call for new investigation. Adverse Drug React Toxicol Rev. 2002;21(3):123–41.CrossRefPubMed Kalapos MP. Carbamazepine-provoked hepatotoxicity and possible aetiopathological role of glutathione in the events. Retrospective review of old data and call for new investigation. Adverse Drug React Toxicol Rev. 2002;21(3):123–41.CrossRefPubMed
4.
go back to reference Harden CL. Therapeutic safety monitoring: what to look for and when to look for it. Epilepsia. 2000;41:37–44.CrossRef Harden CL. Therapeutic safety monitoring: what to look for and when to look for it. Epilepsia. 2000;41:37–44.CrossRef
5.
go back to reference Pearce RE, Vakkalagadda GR, Leeder JS. Pathways of carbamazepine bioactivation in vitro I. Characterization of human cytochromes P450 responsible for the formation of 2- and 3-hydroxylated metabolites. Drug Metab Dispos. 2002;30(11):1170–9.CrossRefPubMed Pearce RE, Vakkalagadda GR, Leeder JS. Pathways of carbamazepine bioactivation in vitro I. Characterization of human cytochromes P450 responsible for the formation of 2- and 3-hydroxylated metabolites. Drug Metab Dispos. 2002;30(11):1170–9.CrossRefPubMed
6.
go back to reference Breton H, Cociglio M, Bressolle F, Peyriere H, Blayac JP, Hillaire-Buys D. Liquid chromatography-electrospray mass spectrometry determination of carbamazepine, oxcarbazepine and eight of their metabolites in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2005;828:80–90.CrossRefPubMed Breton H, Cociglio M, Bressolle F, Peyriere H, Blayac JP, Hillaire-Buys D. Liquid chromatography-electrospray mass spectrometry determination of carbamazepine, oxcarbazepine and eight of their metabolites in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2005;828:80–90.CrossRefPubMed
7.
go back to reference Bu HZ, Kang P, Deese AJ, Zhao P, Pool WF. Human in vitro glutathionyl and protein adducts of carbamazepine-10,11-epoxide, a stable and pharmacologically active metabolite of carbamazepine. Drug Metab Dispos. 2005;33:1920–4.CrossRefPubMed Bu HZ, Kang P, Deese AJ, Zhao P, Pool WF. Human in vitro glutathionyl and protein adducts of carbamazepine-10,11-epoxide, a stable and pharmacologically active metabolite of carbamazepine. Drug Metab Dispos. 2005;33:1920–4.CrossRefPubMed
8.
go back to reference Bertilsson L, Tomson T. Clinical pharmacokinetics and pharmacological effects of carbamazepine and carbamazepine-10,11-epoxide. An update. Clin Pharmacokinet. 1986;11:177–98.CrossRefPubMed Bertilsson L, Tomson T. Clinical pharmacokinetics and pharmacological effects of carbamazepine and carbamazepine-10,11-epoxide. An update. Clin Pharmacokinet. 1986;11:177–98.CrossRefPubMed
9.
go back to reference DeBethizy JD, Hayes JR. Metabolism. A determinant of toxicity. In: Hayes AW, editor. Principles and methods of toxicology. 2nd ed. New York: Raven Press; 1988. p. 29–66. DeBethizy JD, Hayes JR. Metabolism. A determinant of toxicity. In: Hayes AW, editor. Principles and methods of toxicology. 2nd ed. New York: Raven Press; 1988. p. 29–66.
10.
go back to reference Hayes JD, Flanagan JU, Jowsey IR. Glutathione transferases. Annu Rev Pharmacol Toxicol. 2005;45:51–88.CrossRefPubMed Hayes JD, Flanagan JU, Jowsey IR. Glutathione transferases. Annu Rev Pharmacol Toxicol. 2005;45:51–88.CrossRefPubMed
11.
go back to reference Munaka M, Kohshi K, Kawamoto T, Takasawa S, Nagata N, Itoh H, Oda S, Katoh T. Genetic polymorphisms of tobacco- and alcohol-related metabolizing enzymes and the risk of hepatocellular carcinoma. J Cancer Res Clin Oncol. 2003;129:355–60.CrossRefPubMed Munaka M, Kohshi K, Kawamoto T, Takasawa S, Nagata N, Itoh H, Oda S, Katoh T. Genetic polymorphisms of tobacco- and alcohol-related metabolizing enzymes and the risk of hepatocellular carcinoma. J Cancer Res Clin Oncol. 2003;129:355–60.CrossRefPubMed
12.
go back to reference Lin HJ, Han CY, Bernstein DA, Hsiao W, Lin BK, Hardy S. Ethnic distribution of the glutathione transferase Mu 1-1 (GSTM1) null genotype in 1473 individuals and application to bladder cancer susceptibility. Carcinogenesis. 1994;15:1077–81.CrossRefPubMed Lin HJ, Han CY, Bernstein DA, Hsiao W, Lin BK, Hardy S. Ethnic distribution of the glutathione transferase Mu 1-1 (GSTM1) null genotype in 1473 individuals and application to bladder cancer susceptibility. Carcinogenesis. 1994;15:1077–81.CrossRefPubMed
13.
go back to reference Eaton DL, Bammler TK. Concise review of the glutathione S-transferases and their significance to toxicology. Toxicol Sci. 1999;49(2):156–64.CrossRefPubMed Eaton DL, Bammler TK. Concise review of the glutathione S-transferases and their significance to toxicology. Toxicol Sci. 1999;49(2):156–64.CrossRefPubMed
14.
go back to reference Levy M, Goodman MW, Van Dyne BJ, Sumner HW. Granulomatous hepatitis secondary to carbamazepine. Ann Intern Med. 1981;95(1):64–5.CrossRefPubMed Levy M, Goodman MW, Van Dyne BJ, Sumner HW. Granulomatous hepatitis secondary to carbamazepine. Ann Intern Med. 1981;95(1):64–5.CrossRefPubMed
15.
go back to reference Lévy-Chavagnat D. Stratégies de traitement des syndromes épileptiques. Actual Pharm. 2008;475:10–6. Lévy-Chavagnat D. Stratégies de traitement des syndromes épileptiques. Actual Pharm. 2008;475:10–6.
16.
go back to reference Chbili C, B'chir F, Ben Fredj M, Saguem BN, Ben Amor S, Ben Ammou S, Saguem S. Effects of glutathione S-transferase M1 and T1 deletions on epilepsy risk among a Tunisian population. Epilepsy Res. 2014a;108:1168–73.CrossRefPubMed Chbili C, B'chir F, Ben Fredj M, Saguem BN, Ben Amor S, Ben Ammou S, Saguem S. Effects of glutathione S-transferase M1 and T1 deletions on epilepsy risk among a Tunisian population. Epilepsy Res. 2014a;108:1168–73.CrossRefPubMed
17.
go back to reference Chbili C, Bannour S, Khlifi S, Ben Hadj Ali B, Saguem S. Relationships between pharmacokinetic parameters of carbamazepine and therapeutic response in patients with bipolar disease. Ann Biol Clin (Paris). 2014b;72:453–9. Chbili C, Bannour S, Khlifi S, Ben Hadj Ali B, Saguem S. Relationships between pharmacokinetic parameters of carbamazepine and therapeutic response in patients with bipolar disease. Ann Biol Clin (Paris). 2014b;72:453–9.
18.
go back to reference Gara S, Abessi M, Bendjemena K, Abdennebi M, Guemira F. Deletion polymorphism of glutathione S-transferases M1 and T1 in the Tunisian population. Tunis Med. 2010;88(10):700–2.PubMed Gara S, Abessi M, Bendjemena K, Abdennebi M, Guemira F. Deletion polymorphism of glutathione S-transferases M1 and T1 in the Tunisian population. Tunis Med. 2010;88(10):700–2.PubMed
19.
go back to reference Salem AH, Yaqoob A, Ali M, Handu S, Fadel R, Abu-Hijleh M, Almawi W. Genetic polymorphism of the glutathione S-transferase M1 and T1 genes in three distinct Arab populations. Dis Markers. 2011;31(5):311–6.CrossRefPubMedPubMedCentral Salem AH, Yaqoob A, Ali M, Handu S, Fadel R, Abu-Hijleh M, Almawi W. Genetic polymorphism of the glutathione S-transferase M1 and T1 genes in three distinct Arab populations. Dis Markers. 2011;31(5):311–6.CrossRefPubMedPubMedCentral
20.
go back to reference Ueda K, Ishitsu T, Seo T, Ueda N, Murata T, Hori M, Nakagawa K. Glutathione S-transferase M1 null genotype as a risk factor for carbamazepine-induced mild hepatotoxicity. Pharmacogenomics. 2007;8:435–842.CrossRefPubMed Ueda K, Ishitsu T, Seo T, Ueda N, Murata T, Hori M, Nakagawa K. Glutathione S-transferase M1 null genotype as a risk factor for carbamazepine-induced mild hepatotoxicity. Pharmacogenomics. 2007;8:435–842.CrossRefPubMed
21.
go back to reference Gravina P, Spoletini I, Masini S, Valentini A, Vanni D, Paladini E, Bossù P, Caltagirone C, Federici G, Spalletta G, Bernardini S. Genetic polymorphisms of glutathione S-transferases GSTM1, GSTT1, GSTP1and GSTA1 as risk factors for schizophrenia. Psychiatry Res. 2011;187(3):454–6.CrossRefPubMed Gravina P, Spoletini I, Masini S, Valentini A, Vanni D, Paladini E, Bossù P, Caltagirone C, Federici G, Spalletta G, Bernardini S. Genetic polymorphisms of glutathione S-transferases GSTM1, GSTT1, GSTP1and GSTA1 as risk factors for schizophrenia. Psychiatry Res. 2011;187(3):454–6.CrossRefPubMed
22.
go back to reference Cotton SC, Sharp L, Little J, Brockton N. GlutathioneS-transferase polymorphisms and colorectal cancer: a HuGE review. Am J Epidemiol. 2000;151:7–32.CrossRefPubMed Cotton SC, Sharp L, Little J, Brockton N. GlutathioneS-transferase polymorphisms and colorectal cancer: a HuGE review. Am J Epidemiol. 2000;151:7–32.CrossRefPubMed
23.
go back to reference Habdous M, Siest G, Herbeth B, Vincent-Viry M, Visvikis S. Polymorphismes des glutathion S-transférases et pathologies humaines: bilan des études épidémiologiques. Ann Biol Clin. 2004;62:15–24. Habdous M, Siest G, Herbeth B, Vincent-Viry M, Visvikis S. Polymorphismes des glutathion S-transférases et pathologies humaines: bilan des études épidémiologiques. Ann Biol Clin. 2004;62:15–24.
24.
go back to reference Martin NJ, Collier AC, Bowen LD, Pritsos KL, Goodrich GG, Arger K, Cutter G, Pritsos CA. Polymorphisms in the NQO1, GSTT and GSTM genes are associated with coronary heart disease and biomarkers of oxidative stress. Mutat Res. 2009;674(1–2):93–100.CrossRefPubMed Martin NJ, Collier AC, Bowen LD, Pritsos KL, Goodrich GG, Arger K, Cutter G, Pritsos CA. Polymorphisms in the NQO1, GSTT and GSTM genes are associated with coronary heart disease and biomarkers of oxidative stress. Mutat Res. 2009;674(1–2):93–100.CrossRefPubMed
25.
go back to reference Pirmohamed M, Kitteringham NR, Guenthner TM, Breckenridge AM, Park BK. An investigation of the formation of cytotoxic, protein-reactive and stable metabolites from carbamazepine in vitro. Biochem Pharmacol. 1992;43:1675–82.CrossRefPubMed Pirmohamed M, Kitteringham NR, Guenthner TM, Breckenridge AM, Park BK. An investigation of the formation of cytotoxic, protein-reactive and stable metabolites from carbamazepine in vitro. Biochem Pharmacol. 1992;43:1675–82.CrossRefPubMed
26.
go back to reference Roy B, Chowdhury A, Kundu S, Santra A, Dey B, Chakraborty M, Majumder PP. Increased risk of antituberculosis drug –induced hepatotoxicity in individuals with glutathione S-transferase M1 null mutation. J Gastroenterol Hepatol. 2001;16(9):1033–7.CrossRefPubMed Roy B, Chowdhury A, Kundu S, Santra A, Dey B, Chakraborty M, Majumder PP. Increased risk of antituberculosis drug –induced hepatotoxicity in individuals with glutathione S-transferase M1 null mutation. J Gastroenterol Hepatol. 2001;16(9):1033–7.CrossRefPubMed
27.
go back to reference Watanabe I, Tomita A, Shimizu M, Sugawara M, Yasumo H, Koishi R, Takahashi T, Miyoshi K, Nakamura K, Izumi T, Matsushita Y, Furukawa H, Haruyama H, Koga T. A study to survey susceptible genetic factors responsible for troglitazone- associated hepatotoxicity in Japanes patients with type 2 diabetes mellitus. Clin Pharmaco Ther. 2003;73(5):435–55.CrossRef Watanabe I, Tomita A, Shimizu M, Sugawara M, Yasumo H, Koishi R, Takahashi T, Miyoshi K, Nakamura K, Izumi T, Matsushita Y, Furukawa H, Haruyama H, Koga T. A study to survey susceptible genetic factors responsible for troglitazone- associated hepatotoxicity in Japanes patients with type 2 diabetes mellitus. Clin Pharmaco Ther. 2003;73(5):435–55.CrossRef
28.
go back to reference Simon T, Becquemont L, Mary-Krause M, de Waziers I, Beaune P, Funck-Brentano C, Jaillon P. Combined glutathione s-transferases M1 and T1 genetic polymorphism and tacrine hepatotoxicity. Clin Pharmacol Ther. 2000;67(4):432–7.CrossRefPubMed Simon T, Becquemont L, Mary-Krause M, de Waziers I, Beaune P, Funck-Brentano C, Jaillon P. Combined glutathione s-transferases M1 and T1 genetic polymorphism and tacrine hepatotoxicity. Clin Pharmacol Ther. 2000;67(4):432–7.CrossRefPubMed
29.
go back to reference Chbili C, Fathallah N, Nouira M, Laouani A, Hassine A, Ben Amor S, Ben Ammou S, Saguem S. Effects of glutathione S-transferase M1 and T1 deletions on carbamazepine metabolism among a Tunisian population. Genes Genomics. 2015;37(12):991–7.CrossRef Chbili C, Fathallah N, Nouira M, Laouani A, Hassine A, Ben Amor S, Ben Ammou S, Saguem S. Effects of glutathione S-transferase M1 and T1 deletions on carbamazepine metabolism among a Tunisian population. Genes Genomics. 2015;37(12):991–7.CrossRef
Metadata
Title
Glutathione S-transferase M1 and T1 polymorphisms and the risk of mild hepatotoxicity induced by carbamazepine in a tunisian population study
Authors
Chahra Chbili
Anis Hassine
Neila Fathallah
Manel Nouira
Salma Naija
Sofiene Ben Ammou
Saad Saguem
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Neurology / Issue 1/2018
Electronic ISSN: 1471-2377
DOI
https://doi.org/10.1186/s12883-018-1013-8

Other articles of this Issue 1/2018

BMC Neurology 1/2018 Go to the issue