Role of hydrazine in isoniazid-induced hepatotoxicity in a hepatocyte inflammation model

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

“…responsible for the biotransformation of therapeutic agents [e.g., acetaminophen, INH, and rifampicin (RIF)], procarcinogens (e.g., N-nitrosamine), and endogenous compounds (e.g., fatty acids and ketone bodies) (14)(15)(16). Antituberculosis (anti-TB) drug-induced hepatitis is one of the most prevalent drug-induced liver injuries in many countries (17,18).…”

“…Antituberculosis (anti-TB) drug-induced hepatitis is one of the most prevalent drug-induced liver injuries in many countries (17,18). CYP2E1-mediated INH metabolism may result from oxidative stress through the production of toxic metabolites or free radicals and lead to drug-induced hepatotoxicity (15,16).…”

“…The primary pathway of INH metabolism involves acetylation by N-acetyltransferase (NAT2) in the liver to generate acetyl-INH. Acetyl-INH undergoes hydrolysis to form acetyl-hydrazine and the nontoxic substance isonicotinic acid (INA), which is oxidized by CYP2E1 to form reactive acylating hepatotoxins, possibly acetyldiazene, or its breakdown products consisting of an acetyl radical, an acetylonium ion, and a ketene (16,17) [Electronic Supplementary Materials (ESM) Fig. 1].…”

“…Timbrell et al (23) have reported that acetylhydrazine is the toxic metabolite responsible for liver injury caused by INH. RIF is a potent inducer of CYP2E1, and it could aggravate INH-induced hepatotoxicity by increasing the production of toxic metabolites such as hydrazine in man and rats (16,24,27). A few studies have shown that hepatic CYP2E1 activity highly correlates with INH-induced hepatotoxicity (15,17).…”

“…Hydrazine reacts with a sulfhydryl group, which results in GSH depletion within the hepatocytes and leads to cell death (12,28,29). The molecular mechanism of hydrazine-induced hepatotoxicity has been attributed to oxidative stress due to the formation of reactive oxygen species (ROS) and carbonyl (16). These findings suggest that CYP2E1 could play an important role in the adaptive response against the CYP2E1-dependent oxidative stress caused by INH and RIF.…”