1-Aminobenzotriazole (ABT) is an orally active nonspecific and irreversible inhibitor of cytochrome P450 (CYP)[1]. 1-Aminobenzotriazole is a substrate and inhibitor of N-acetyltransferase (NAT)[2].
In vitro, 1-Aminobenzotriazole (1mM) treatment of sandwich cultured human hepatocytes (SCHH) for 0-60min significantly inhibited the intracellular activities of CYP3A, CYP2C9, CYP2D6 and CYP1A2. The residual activity of CYP3A was 3% of the control, while the residual activities of CYP2C9, CYP2D6 and CYP1A2 remained between 5% and 35%[3].
In vivo, oral administration of 1-Aminobenzotriazole (0, 50, 100, 200, 300mg/kg) to SD rats significantly inhibited the hepatic metabolism of MDZ, but could not completely inhibit the formation of 1'-OH MDZ[4]. Oral administration of 1-Aminobenzotriazole (50mg/kg) to male mice for 3 days suppressed the dominant lethal effect of acrylamide-induced spermatocytes[5]. Treatment of rats with 1-Aminobenzotriazole (78mg/kg) increased organ weights and mortality, and increased sensitivity to inflammation-induced multiple organ failure (MOF)[6].
References:
[1] de Montellano P R O. 1-Aminobenzotriazole: a mechanism-based cytochrome P450 inhibitor and probe of cytochrome P450 biology[J]. Medicinal chemistry, 2018, 8(3).
[2] Sun Q, Harper T W, Dierks E A, et al. 1-Aminobenzotriazole, a known cytochrome P450 inhibitor, is a substrate and inhibitor of N-acetyltransferase[J]. Drug metabolism and disposition, 2011, 39(9): 1674-1679.
[3] Kimoto E, Walsky R, Zhang H, et al. Differential modulation of cytochrome P450 activity and the effect of 1-aminobenzotriazole on hepatic transport in sandwich-cultured human hepatocytes[J]. Drug Metabolism and Disposition, 2012, 40(2): 407-411.
[4] Parrish K E, Mao J, Chen J, et al. In vitro and in vivo characterization of CYP inhibition by 1‐aminobenzotriazole in rats[J]. Biopharmaceutics & drug disposition, 2016, 37(4): 200-211.
[5] Adler I D, Baumgartner A, Gonda H, et al. 1-Aminobenzotriazole inhibits acrylamide-induced dominant lethal effects in spermatids of male mice[J]. Mutagenesis, 2000, 15(2): 133-136.
[6] Carcillo J, Kost C, Korzekwa K, et al. 1-aminobenzotriazole (ABT), the cytochrome P450 suicide inhibitor, sensitizes rats to zymosan induced-multiple organ failure184[J]. Pediatric Research, 1998, 43(4): 34-34.
1-Aminobenzotriazole (ABT)是具有口服活性的细胞色素P450（CYP）的非特异性和不可逆抑制剂[1]。1-Aminobenzotriazole是N-乙酰转移酶（NAT）的底物和抑制剂[2]。
在体外，1-Aminobenzotriazole（1mM）处理三明治培养的人肝细胞（SCHH）0-60min，显著抑制了细胞内CYP3A、CYP2C9、CYP2D6和CYP1A2活性，CYP3A的残留活性为对照的3%，CYP2C9、CYP2D6和CYP1A2的残留活性保持在5%至35%之间[3]。
在体内，SD大鼠预先口服1-Aminobenzotriazole（0, 50, 100, 200, 300mg/kg），可以显著抑制MDZ的肝脏代谢，但不能完全抑制1'-OH MDZ的生成[4]。雄性小鼠预先口服1-Aminobenzotriazole（50mg/kg）3天，抑制了丙烯酰胺诱导的精子细胞显性致死效应[5]。1-Aminobenzotriazole（78mg/kg）治疗大鼠，增加了器官重量和死亡率，增加了对炎症诱导的多器官衰竭（MOF）的敏感性[6]。