Mechanisms of isoniazid and rifampicin-induced liver injury and the effects of natural medicinal ingredients: A review

Abstract

Isoniazid (INH) and rifampicin (RFP) are the first-line medications for tuberculosis treatment, and liver injury is the major adverse effect. Natural medicinal ingredients provide distinct benefits in alleviating patients’ symptoms, lowering the liver injury risk, delaying disease progression, and strengthening the body’s ability to heal. This paper summarises the recent research on the mechanisms of INH and RFP-induced liver injury and the effects of natural medicinal ingredients. It is believed that INH-induced liver injury may be attributed to oxidative stress, mitochondrial dysfunction, drug metabolic enzymes, protoporphyrin IX accumulation, endoplasmic reticulum stress, bile transport imbalance, and immune response. RFP-induced liver injury is mainly related to cholestasis, endoplasmic reticulum stress, and liver lipid accumulation. However, the combined effect of INH and RFP on liver injury risk is still uncertain. RFP can increase INH-induced hepatotoxicity by regulating the expression of drug-metabolizing enzymes and transporters. In contrast, INH can antagonize RFP-induced liver injury by reducing the total bilirubin level in the blood. Sagittaria sagittifolia polysaccharide, quercetin, gallic acid, and other natural medicinal ingredients play protective roles on INH and RFP-induced liver injury by enhancing the body’s antioxidant capacity, regulating metabolism, inhibiting cell apoptosis, and reducing the inflammatory response. There are still many gaps in the literature on INH and RFP-induced liver injury mechanisms and the effects of natural medicinal ingredients. Thus, further research should be carried out from the perspectives of liver injury phenotype, injury markers, in vitro and in vivo liver injury model construction, and liver-gut axis. This paper comprehensively reviewed the literature on mechanisms involved in INH and RFP-induced liver injury and the status of developing new drugs against INH and RFP-induced liver injury. In addition, this review also highlighted the uses and advantages of natural medicinal ingredients in treating drug-induced liver injury.

Severe dengue infection unmasking drug‐induced liver injury: Successful management with N‐acetylcysteine

“…17 We theorize that infection-related hepatic dysfunction may have reduced clearance of these agents' metabolites, leading to toxic accumulation. 18 Additionally, the aberrant T-cell activation characteristic of severe dengue could facilitate immunemediated hepatotoxicity via cross-reactivity. 19 Given the critical condition and high mortality risk (up to 13%) associated with severe dengue, 20 our initial focus was on shock management and addressing coagulopathy.…”

“…First‐line ATT agents like rifampin and isoniazid rely on extensive hepatic metabolism and exhibit dose‐dependent hepatotoxicity profiles 17 . We theorize that infection‐related hepatic dysfunction may have reduced clearance of these agents' metabolites, leading to toxic accumulation 18 . Additionally, the aberrant T‐cell activation characteristic of severe dengue could facilitate immune‐mediated hepatotoxicity via cross‐reactivity 19 …”

A near‐infrared fluorescent probe for detecting hydrazine metabolized from isoniazid in living cells

“…In addition, these hepatotoxic metabolites induced the excessive production of reactive oxygen species (ROS) and reactive nitrogen species in liver cells after being metabolized by enzymes, including CYP2E1. Elevation of hepatic CYP2E1 plays an important role in the development of isoniazid hepatotoxicity through the generation of free radicals from N 2 H 4 [3,4]. Previous studies have shown that N 2 H 4 induces steatosis by altering the liver gene expression profile, leading to the production of liver lipids and intracellular transport, rather than the removal of fatty acid metabolites [4][5][6].…”

Asiatic acid ameliorates rifampicin‐ and isoniazid‐induced liver injury in vivo by regulating sphingolipid metabolism and mitogen‐activated protein kinase signalling pathways

“…Toxic parent drugs and their metabolic products may cause inflammation in the liver. Toxic metabolites of INH cause cell membrane peroxidation and disruption of mitochondrial metabolism, resulting in the release of excess free radicals and subsequent hepatocyte death 9 . RFP hastens INH metabolism by upregulating the expression levels of hepatic microsomal enzymes, thereby aggravating injury 10 .…”

“…Toxic metabolites of INH cause cell membrane peroxidation and disruption of mitochondrial metabolism, resulting in the release of excess free radicals and subsequent hepatocyte death. 9 RFP hastens INH metabolism by upregulating the expression levels of hepatic microsomal enzymes, thereby aggravating injury. 10 However, the underlying mechanisms causing inflammation and oxidative stress in liver injury remain unknown.…”