{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nN‐acetyltransferase 2 (NAT2) is a polymorphic phase II xenobiotic‐metabolizing enzyme that catalyzes the acetylation of aromatic amines and hydrazine drugs. This enzyme plays a dual role by participating in both detoxification and bioactivation processes for environmental chemicals—such as those encountered in tobacco smoke and high‐temperature cooked meat—and therapeutic agents. Population studies have documented marked ethnic and geographic variability in NAT2 allele frequencies, and structural investigations have elucidated key features underlying its substrate specificity and genetic diversity. These findings underscore the evolutionary pressures acting on NAT2 and establish its importance in interindividual variability in xenobiotic metabolism."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNAT2 is central to the metabolism of several clinically important drugs. In the context of antituberculosis therapy, NAT2 acetylates isoniazid—the drug primarily implicated in drug‐induced hepatotoxicity. Multiple studies have shown that individuals with slow acetylator genotypes accumulate hepatotoxic intermediates, thereby increasing their risk for antituberculosis drug–induced liver injury. Similar genotype–phenotype associations have been observed with other medications, as NAT2 genotype has been used to predict isoniazid clearance and to guide personalized dosing strategies for drugs such as sulfasalazine. These observations establish NAT2 as a critical determinant in drug disposition and toxicity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond drug metabolism, NAT2 modulates the bioactivation of potential carcinogens, thereby influencing cancer susceptibility in gene–environment interaction contexts. Studies in bladder cancer, for example, have documented that slow acetylators are at greater risk when exposed to tobacco‐derived arylamines and occupational carcinogens, whereas interactions with other metabolizing enzymes further modify risk. Similar relationships have been reported in colorectal cancer, where NAT2 polymorphisms—often in concert with variations in NAT1 or CYP1A2—appear to modulate the carcinogenic effects of heterocyclic amines from well‐done meat. Additional investigations have highlighted associations between NAT2 acetylator status and risks for laryngeal, orofacial, breast, and even gastric or esophageal cancers, with smoking and dietary exposures frequently acting as strong modifiers. Collectively, these findings support a functional role for NAT2 in determining individual susceptibility to cancer through its effects on carcinogen metabolism."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging studies continue to expand the clinical and biological implications of NAT2 variation. Recent work has linked a nonsynonymous NAT2 variant not only to altered enzymatic activity but also to differences in insulin sensitivity, thereby broadening the enzyme’s impact to metabolic regulation. Moreover, further population‐based investigations into drug‐induced liver injury emphasize the promise of NAT2 genotyping as a tool for personalized medicine. These additional perspectives highlight the diverse roles of NAT2 in both pharmacokinetics and disease susceptibility, reaffirming its status as a key mediator at the interface of environmental exposures and human health."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "32", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "S Garte, L Gaspari, A K Alexandrie, et al. 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