Genetic Polymorphisms and Toxicities of First-Line Antituberculosis Drugs: Systematic Review of the Literature

Abstract

Introduction: Polymorphisms are the main genetic factors associated with toxicities of antituberculosis drugs. This literature review summarizes the polymorphisms of the genes that code for the enzymes of the metabolism of antituberculosis drugs and their transmembrane transporters. Some mechanisms of drug-associated toxicities and strategies for their management have also been described in this review. Methods: The bibliographic searches were exclusively carried out in PubMed, over a period of ten years (2010-2020). The search terms were the words "toxicity + antituberculosis drug + one or two word(s) among the following: polymorphism, genetics, mutation, SNP, HLA or haplotype". Publications in English or French, relating to the various toxicities associated with first-line anti-tuberculosis drugs (Rifampicin, Isoniazid, Ethambutol and Pyrazinamide) administered to patients with pulmonary tuberculosis, extrapulmonary tuberculosis or co-infected with TB/HIV were included in this review. Duplicates, in vitro, in silico or drug-induced toxicity studies other than antituberculosis drugs and genetic mutations of Mycobacteria strains were not included. Results: The studies selected and included were case reports, cohort studies, original research, systematic reviews and meta-analyses on human subjects of different ethnic origins. Hepatotoxicity is the most common toxicity associated with NAT2, CYP2E1, GSTM1 and GSTT1 polymorphisms in patients on antituberculosis drugs. Other forms of toxicity, less frequent, occurring in certain patients under concomitant treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), antiretrovirals (ARVs), antibiotics or antiepileptics have also been identified. Conclusion: The genetic polymorphisms associated with the toxicities of antituberculosis drugs concern both the main enzymes of the metabolic pathways (NAT2, CYP2E1, GST) and the transmembrane transporters (SLCO1B1 and ABCB1).

Traditional Medicinal Plants with Significant Protection Against Antitubercular Drug-induced Liver Injury: A Systematic Review

“…Tuberculosis (TB) remains a lethal communicable ailment of global public health concern despite the intensified research to understand and eradicate it. [1][2][3] In 2021, about 10.6 million people were estimated to fall ill with TB worldwide with the incident rate rising by 3.6% between 2020 and 2021 with eight countries having two-thirds of the disease's global burden. 4, 5 The emergence of drug resistant TB continues to undermine the gains of global eradication efforts and as such TB has remained a public health scourge.…”