Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis

Abstract

Most cases with antituberculosis drug-induced hepatitis have been attributed to isoniazid. Isoniazid is metabolized by hepatic N-acetyltransferase (NAT) and cytochrome P450 2E1 (CYP2E1) to form hepatotoxins. However, the role of CYP2E1 in this hepatotoxicity has not yet been reported. The aim of this study was to evaluate whether the polymorphism of the CYP2E1 gene is associated with antituberculosis drug-induced hepatitis. A total of 318 tuberculosis patients who received antituberculosis treatment were followed prospectively. Their CYP2E1 and NAT2 genotypes were determined using a polymerase chain reaction with restriction fragment length polymorphism method. Twenty-one healthy volunteers were recruited for CYP2E1 phenotype study using a chlorzoxazone test. Forty-nine (15.4%) patients were diagnosed to have drug-induced hepatotoxicity. Patients with homozygous wild genotype CYP2E1 c1/c1 had a higher risk of hepatotoxicity (20.0%; odds ratio [OR], 2.52) than those with mutant allele c2 (CYP2E1 c1/c2 or c2/c2, 9.0%, P ‫؍‬ .009). If CYP2E1 c1/c2 or c2/c2 genotype combined with rapid acetylator status was regarded as the reference group, the risk of hepatotoxicity increased from 3.94 for CYP2E1 c1/c1 with rapid acetylator status to 7.43 for CYP2E1 c1/c1 with slow acetylator status. After adjustment for acetylator status and age, the CYP2E1 c1/c1 genotype remained an independent risk factor for hepatotoxicity (OR, 2.38; P ‫؍‬ .017). Furthermore, under the administration of isoniazid, the volunteers with CYP2E1 c1/c1 genotype had higher CYP2E1 activity than those with other genotypes had and, hence, might produce more hepatotoxins. In conclusion, CYP 2E1 genetic polymorphism may be associated with susceptibility to antituberculosis drug-induced hepatitis. (HEPATOLOGY 2003;37:924-930.)

Drug-induced liver injury in older adults

“…Pharmacometabolonomics may help predict individuals at risk of paracetamol hepatotoxicity in the future [Winnike et al 2010]. [Kumar et al 2010;Daly et al 2009;Myers et al 2008;Hilmer et al 2007b;Maddrey, 2005;Schmidt, 2005;Huang et al 2003;Lee, 2003;Kaplowitz, 2001;Pande et al 1996;Banks et al 1995 Therapeutic Advances in Drug Safety 1 (2) Diclofenac Diclofenac is a NSAID widely used for treatment of a variety of rheumatoid disorders. Diclofenac use is associated with raised liver function tests in 1020% of patients and rarely with idiosyncratic serious hepatotoxicity, for which metabolic risk factors have been identified [Maddrey, 2005;Rostom et al 2005;Boelsterli, 2003].…”

“…Liver injury from isoniazid seems to be mediated by the toxic metabolite hydrazine and its monoacetyl derivative [Yue et al 2004]. Risk factors for toxicity include regular to heavy alcohol consumption, induction of CYP2E1 [Maddrey, 2005;Pande et al 1996], slow acetylators [Pugh et al 2009;Huang et al 2003] and female gender [Maddrey, 2005], as described in Table 3.…”

Pharmacogenomics: Challenges and Opportunities

“…Because these reactions often occur in an apparently unpredictable fashion, they have been termed "idiosyncratic," and a genetic predisposition is often invoked. Accrual of patient sets in which to test this idea will require multi-center collaborations (46), and the initial focus of genetic analysis has been on a small number of genes chosen because they may be associated with disease susceptibility (41,42,(47)(48)(49)(50).…”

Protective Effects of Kaempferol on Isoniazid- and Rifampicin-Induced Hepatotoxicity

“…CYP2E1 can be induced by ethanol, drugs such as isoniazid (INH), and hydrocarbons (12,13). CYP2E1 is Electronic supplementary material The online version of this article (doi:10.1208/s12248-013-9490-6) contains supplementary material, which is available to authorized users.…”