Isoniazid bioactivation

Isoniazid (INH) Inhibits mycolic acid synthesis high level resistance—deletions in katG gene (encodes catalase needed for INH bioactivation) low-level resistance—deletions in inhA gene (encodes acyl carrier protein, the target ). Hepatitis (age-dependent), peripheral neuritis (use vitamin B6), hemolysis in G6PD deficiency, SLE in slow acetylators (rare)... 

Mutations in the kcUG gene result in the underproduction of mycobacterial catalase, an enzyme that bioactivates INH. facilitating its interaction with its target, keto-acyl carrier protein synthetase. The result is high-level resistance to isoniazid but without cross-resistance to pyrazinamide. Mutations in the inhA gene result in low-level resistance, with cross-resistance to pyrazinamide. The answer is (B). 

Some examples of free-radicals generated by the bioactivation of drug molecules are shown in Fig. 10.31. Isoniazid is acetylated to its major metabolite acetylisoniazid, which is hydrolyzed to acetylhydrazine and isonicotinic acid (Fig. 10.31-1). Acetylhydrazine is further metabolized by the CYP2E1 to an N-hydroxy intermediate that hydrates into an acetyl radical, which can then initiate the process that leads to hepatic necrosis. Other carbon-centered radicals are formed from hydrazines such as the antihypertensive hydralazine, and thio-radicals from the ACE inhibitor captopril (Fig. 10.31-2 and -3). 

Chien JY, Peter RM, Nolan CM, Wartell C, Slattery JT, Nelson SD, Carithers RL, Thummel KE. Influence of pol3fmorphic AT-acetyltransferase phenotype cn the inhibition and induction of acetaminophen bioactivation widi long-term isoniazid inPharmacolTher( 99T)6 24-34. 

---