ArticleChemical research in toxicology2016
Bioactivation of Heterocyclic Aromatic Amines by UDP Glucuronosyltransferases.
Article in Chemical research in toxicology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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8 citing papers in PubMed, 34 citations in OpenAlex.
- Prevalence and patterns of mutations in RAS/RAF/MEK/ERK/MAPK signaling pathway in colorectal cancer in North Africa.BMC cancer · 2022Review
- Metabolism and biomarkers of heterocyclic aromatic amines in humans.Genes and environment : the official journal of the Japanese Environmental Mutagen Society · 2021Review
- Sulforaphane suppresses carcinogenesis of colorectal cancer through the ERK/Nrf2‑UDP glucuronosyltransferase 1A metabolic axis activation.Oncology reports · 2020Article
- Evaluation of Tobacco Smoke and Diet as Sources of Exposure to Two Heterocyclic Aromatic Amines for the U.S. Population: NHANES 2013-2014.Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2020Article
- The development and prevalidation of an in vitro mutagenicity assay based on MutaMouse primary hepatocytes, Part II: Assay performance for the identification of mutagenic chemicals.Environmental and molecular mutagenesis · 2019Article
- The development and prevalidation of an in vitro mutagenicity assay based on MutaMouse primary hepatocytes, Part I: Isolation, structural, genetic, and biochemical characterization.Environmental and molecular mutagenesis · 2019Article
- Biomonitoring an albumin adduct of the cooked meat carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in humans.Carcinogenesis · 2018Article
- Metabolism of the Tobacco Carcinogen 2-Amino-9H-pyrido[2,3-b]indole (AαC) in Primary Human Hepatocytes.Chemical research in toxicology · 2017Article
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3 authors at 1 institution in 1 country.
Funding
Abstract
2-Amino-9H-pyrido[2,3-b]indole (AαC) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are carcinogenic heterocyclic aromatic amines (HAA) that arise during the burning of tobacco and cooking of meats. UDP-glucuronosyltransferases (UGT) detoxicate many procarcinogens and their metabolites. The genotoxic N-hydroxylated metabolite of AαC, 2-hydroxyamino-9H-pyrido[2,3-b]indole (HONH-AαC), undergoes glucuronidation to form the isomeric glucuronide (Gluc) conjugates N(2)-(β-d-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AαC-HON(2)-Gluc) and O-(β-d-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AαC-HN(2)-O-Gluc). AαC-HON(2)-Gluc is a stable metabolite but AαC-HN(2)-O-Gluc is a biologically reactive intermediate, which covalently adducts to DNA at levels that are 20-fold higher than HONH-AαC. We measured the rates of formation of AαC-HON(2)-Gluc and AαC-HN(2)-O-Gluc in human organs: highest activity occurred with liver and kidney microsomes, and lesser activity was found with colon and rectum microsomes. AαC-HN(2)-O-Gluc formation was largely diminished in liver and kidney microsomes, by niflumic acid, a selective inhibitor UGT1A9. In contrast, AαC-HON(2)-Gluc formation was less affected and other UGT contribute to N(2)-glucuronidation of HONH-AαC. UGT were reported to catalyze the formation of isomeric Gluc conjugates at the N(2) and N3 atoms of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (HONH-PhIP), the genotoxic metabolite of PhIP. However, we found that the N3-Gluc of HONH-PhIP also covalently bound to DNA at higher levels than HONH-PhIP. The product ion spectra of this Gluc conjugate acquired by ion trap mass spectrometry revealed that the Gluc moiety was linked to the oxygen atom of HONH-PhIP and not the N3 imidazole atom of the oxime tautomer of HONH-PhIP as was originally proposed. UGT1A9, an abundant UGT isoform expressed in human liver and kidney, preferentially forms the O-linked Gluc conjugates of HONH-AαC and HONH-PhIP as opposed to their detoxicated N(2)-Gluc isomers. The regioselective O-glucuronidation of HONH-AαC and HONH-PhIP, by UGT1A9, is a mechanism of bioactivation of these ubiquitous HAAs.
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