Antitubercular drugs induced liver injury: an updated insight into molecular mechanisms.

Devaraj Ezhilarasan

Drug metabolism reviews 2023 Aug

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Tuberculosis (TB) remains a major global health burden. Antitubercular drugs (ATDs) such as isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), and ethambutol are used as first-line therapy in TB patients. Drug-induced liver injury is one of the common side effects that leads to the discontinuation of ATDs in TB patients. Therefore, this review discusses the molecular pathogenesis of ATDs induced liver injury. The biotransformation of INH, RIF, and PZA in the liver liberates several reactive intermediates, leading to peroxidation of the hepatocellular membrane and oxidative stress. INH + RIF administration decreased the expression of bile acid transporters such as the bile salt export pump and multidrug resistance-associated protein 2 and induced liver injury by sirtuin 1 and farnesoid X receptor pathway. INH inhibits the nuclear translocation of Nrf2 by interfering with its nuclear importer, karyopherin β1, thereby inducing apoptosis. INF + RIF treatments alter Bcl-2 and Bax homeostasis, mitochondrial membrane potential, and cytochrome c release, thereby triggering apoptosis. RIF administration enhances the expression of genes involved in fatty acid synthesis and hepatocyte fatty acid uptake (CD36). RIF induces the expression of peroxisome proliferator-activated receptor -γ and its downstream proteins and perilipin-2 by activating the pregnane X receptor in the liver to increase fatty infiltration into the liver. ATDs administration induces oxidative stress, inflammation, apoptosis, cholestasis, and lipid accumulation in the liver. However, ATDs toxic potentials are not elaborately studied at the molecular level in clinical samples. Therefore, future studies are warranted to explore ATDs induced liver injuries at the molecular level in clinical samples whenever possible.

Citation

Devaraj Ezhilarasan. Antitubercular drugs induced liver injury: an updated insight into molecular mechanisms. Drug metabolism reviews. 2023 Aug;55(3):239-253