Distribution of allelic and genotypic frequencies of NAT2 and CYP2E1variants in Moroccan population

Abstract

BackgroundSeveral pathogenesis and genetic factors influence predisposition to antituberculosis drug-induced hepatotoxicity (ATDH) especially for isoniazid (INH). However, the major susceptibility genes for ATDH are N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1). NAT2 gene determines the individual’s acetylator status (fast, intermediate or slow) to metabolize drugs and xenobiotics, while CYP2E1 c1/c1 genotype carriers had an increased risk of ATDH.Polymorphisms of the NAT2 and CYP2E1 genes vary remarkably among the populations of different ethnic origins.The aim of this study was to determine, for the first time, the frequency of slow acetylators in Moroccan population by genotyping of NAT2 gene variants and determining the genotype c1/c1 for CYP2E1 gene, in order to predict adverse effects of Tuberculosis treatment, particularly hepatotoxicity.ResultsThe frequencies of specific NAT2 alleles were 53%, 25%, 2% and 4% for NAT2*5, NAT2*6, NAT2*7 and NAT2*14 respectively among 163 Moroccan studied group. Genotyping of CYP2E1 gene, by real-time polymerase chain reaction using TaqMan probes, revealed frequencies of 98.5% for c1/c1 and 1.5% for c1/c2 among 130 Moroccan studied group.ConclusionThe most prevalent genotypes of NAT2 gene in Moroccans are those which encode slow acetylation phenotype (72.39%), leading to a high risk of ATDH. Most Moroccans are homozygous for c1 allele of CYP2E1 gene which aggravates hepatotoxicity in slow acetylators.This genetic background should be taken into account in determining the minimum dose of INH needed to treat Moroccan TB patients, in order to decrease adverse effects.

Rol de la farmacogenómica en el régimen de tratamiento de tuberculosis

“…Otros países ya han reportado los genotipos de NAT2 en sus poblaciones, entre ellos están, China (28) , México (28)(29)(30) , Morocco (31) , India (32) y Brasil (33) , encontrado diferencias en sus genotipos comparados con los de otras poblaciones. La Tabla 2a muestra un metaanálisis de las frecuencias de los alelos de NAT2 en nueve poblaciones (31) .…”

“…La Tabla 2a muestra un metaanálisis de las frecuencias de los alelos de NAT2 en nueve poblaciones (31) .…”

“…Se ha reportado que el gen CYP2E1 tiene varios polimorfismos, pero solo uno (rs2031920 (-1053 C>T)) ha sido extensamente evaluado en asociación con las drogas antituberculosas, este polimorfismo puede afectar la actividad de la enzima (31,35) . El genotipo (C/C) ha sido asociado a la reducción de actividad metabólica (metabolizador lento) de CYP2E1 y así causando un alto riesgo de hepatotoxicidad.…”

“…El genotipo (C/C) ha sido asociado a la reducción de actividad metabólica (metabolizador lento) de CYP2E1 y así causando un alto riesgo de hepatotoxicidad. La tabla 2b muestra un metaanálisis de las frecuencias de los genotipos reportados para CYP2E1, en el cual se demuestra la variación genética entre diferentes poblaciones (31) .…”

Hepatotoxicity in Rats Induced by Aqueous Extract of Polygoni Multiflori Radix, Root of Polygonum multiflorum Related to the Activity Inhibition of CYP1A2 or CYP2E1

“…Polymorphisms have been reported to be related to hepatotoxicity of some drugs in the affected individuals [19, 20]. CYP1A2 and CYP2E1 mainly exist in the liver, accounting for 13% and 7% of total CYP450 enzymes, respectively [21].…”