2-Amino-9H-pyrido[2,3-b]indole (AalphaC) and 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAalphaC) are two mutagenic and carcinogenic heterocyclic amines formed during ordinary cooking. In this study, we have investigated the in vitro metabolism of tritium-labelled AalphaC and MeAalphaC in hepatic microsomes from human pools, rats induced with polychlorinated biphenyl (PCB) (Aroclor 1254) and control rats. The microsomes were incubated with AalphaC and MeAalphaC and the detoxified and activated metabolites of AalphaC and MeAalphaC were separated and characterised by HPLC-MS. AalphaC is metabolised to two major and three minor detoxified metabolites, while MeAalphaC is metabolised to three major and one minor detoxified metabolites. Some AalphaC and MeAalphaC are activated by oxidation to the reactive metabolites N-2-OH-AalphaC and N-2-OH-MeAalphaC, respectively. These reactive N-2-OH-metabolites react partially in the incubation system with formation of protein adducts, dimers and the parent compound by reduction of the A(2)-OH-metabolites. The distribution between the detoxified and activated metabolites in the different types of hepatic microsomes showed same pattern for both AalphaC and McAalphaC In PCB-induced rat microsomes, the major part of the metabolites are detoxified, only a little amount is activated. In control rat microsomes there is a fifty-ffty distribution between detoxification and activation, while the major part of the metabolites from the human microsomes are activated and reacts to form dimers and protein adducts. These data show that, in human hepatic microsomes compared to rat hepatic microsomes, a major part of AalphaC and MeAalphaC are metabolically activated to the reactive N-2-OH-AalphaC and N-2-OH-MeAalphaC.
Frederiksen, H., & Frandsen, H. L. (2002). In vitro metabolism of two heterocyclic andnes, 2-amino-9H-pyrido[2,3-b]indole (A alpha C) and 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA alpha C) in human and rat hepatic microsomes. Pharmacology & Toxicology, 90(3), 127-134. https://doi.org/10.1034/j.1600-0773.2002.900303.x