3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), a food-born carcinogenic heterocyclic amine, promotes nitric oxide production in murine macrophages.
A heterocyclic amine, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) is one of the potent food-born dietary carcinogens derived mainly from burnt meat products. In the present study, we investigated the inductive effect of Trp-P-1 on nitric oxide (NO) production in murine macrophages since NO and its oxidized derivatives are directly involved in triggering mutagenesis and carcinogenesis. Our results show that Trp-P-1 induced mRNA expression of inducible NO synthase (iNOS) and NO production without co-stimulation in murine peritoneal macrophages and RAW 264.7 cells. Trp-P-1 further enhanced both iNOS mRNA expression and NO production, which were primarily induced by lipopolysaccharide (LPS). Electrophoretic mobility shift assay demonstrated that Trp-P-1, alone or in the presence of LPS, facilitated the DNA binding activity of the transcription factor NF-kappaB, and the trans-acting activity of the NF-kappaB was confirmative as determined by in vitro transfection and a luciferase reporter gene assay. Moreover, Trp-P-1 induced increasing intracellular reactive oxygen species (ROS), which play an important role in NF-kappaB activation. These results suggest that Trp-P-1 induces NO production mediated by an increased intracellular ROS, NF-kappaB activation, and subsequent iNOS gene expression.
Yun
Cheol-Heui
CH
Laboratory Sciences Division, International Vaccine Institute, SNU Research Park, San 4-8 Bongcheon-7 dong, Kwanak-gu, Seoul 151-818, Republic of Korea.
Jung
Uhee
U
Son
Chang Gue
CG
Ju
Hyang Ran
HR
Han
Seung Hyun
SH
D000818:Animals; D002243:Carbolines / Q000633:toxicity*; D002460:Cell Line; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009153:Mutagens / Q000633:toxicity; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
D002243:Carbolines; D008070:Lipopolysaccharides; D009153:Mutagens; D016328:NF-kappa B; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C019132:3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole