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Cited by 314Pharmacogenetics and Drug MetabolismMetal-Catalyzed Oxygenation MechanismsTryptophan and brain disorders

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Oxidation of Indole by Cytochrome P450 Enzymes

Gillam, Elizabeth M. J., Notley, Lisa M., Cai, Hongliang, De Voss, James J., Guengerich, F. Peter·2000·Biochemistry
DOI 10.1021/bi001229u
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Abstract

Indole is a product of tryptophan catabolism by gut bacteria and is absorbed into the body in substantial amounts. The compound is known to be oxidized to indoxyl and excreted in urine as indoxyl (3-hydroxyindole) sulfate. Further oxidation and dimerization of indoxyl leads to the formation of indigoid pigments. We report the definitive identification of the pigments indigo and indirubin as products of human cytochrome P450 (P450)-catalyzed metabolism of indole by visible, (1)H NMR, and mass spectrometry. P450 2A6 was most active in the formation of these two pigments, followed by P450s 2C19 and 2E1. Additional products of indole metabolism were characterized by HPLC/UV and mass spectrometry. Indoxyl (3-hydroxyindole) was observed as a transient product of P450 2A6-mediated metabolism; isatin, 6-hydroxyindole, and dioxindole accumulated at low levels. Oxindole was the predominant product formed by P450s 2A6, 2E1, and 2C19 and was not transformed further. A stable end product was assigned the structure 6H-oxazolo[3,2-a:4, 5-b']diindole by UV, (1)H NMR, and mass spectrometry, and we conclude that P450s can catalyze the oxidative coupling of indoles to form this dimeric conjugate. On the basis of these results, we propose that the P450/NADPH-P450 reductase system can catalyze oxidation of indole to a variety of products.

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Metadata

Authors
Gillam, E. M. J., Notley, L. M., Cai, H., De Voss, J. J., & Guengerich, F. P.
Affiliations
  • The University of Queensland (AU)
  • Departments of Physiology and Pharmacology and Chemistry, The University of Queensland, Brisbane, Queensland, Australia, 4072 and Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232
Corresponding author
  • Gillam, Elizabeth M. J.
  • Guengerich, F. Peter
ORCID
Venue
Biochemistry
Publisher
American Chemical Society (ACS)
Published
2000-10-13
Volume
39
Issue
45
Pages
13817-13824
ISSN
  • 0006-2960 (ISSN-L)
  • 1520-4995
DOI
10.1021/bi001229u
OpenAlex
W1986333080
Cited by
313
References
13
Citations by year
2026: 13 · 2025: 10 · 2024: 13 · 2023: 13 · 2022: 17 · 2021: 17 · 2020: 21 · 2019: 17 · 2018: 11 · 2017: 10 · 2016: 11 · 2015: 15 · 2014: 10 · 2013: 12 · 2012: 7
FWCI
3.91
Type
journal article
Language
en
Open access
closed
Locations
  • Biochemistry (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r35ca044353-14)
  • National Cancer Institute (R35-CA44353)
  • National Institute of Environmental Health Sciences (P30 ES-00267, P30ES000267)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
indole oxidation, cytochrome P450, CYP2A6, CYP2C19, CYP2E1, indigo, indirubin, indoxyl, tryptophan catabolism, oxidative coupling, NADPH-cytochrome P450 reductase, indoxyl sulfate, gut microbiota
MeSH terms
Animals, Aryl Hydrocarbon Hydroxylases, Cytochrome P-450 Enzyme System, Escherichia coli, Humans, Mixed Function Oxygenases, Indigo Carmine, Indoles, Isatin, Male, Microsomes, Liver, NADH, NADPH Oxidoreductases, NADPH-Ferrihemoprotein Reductase, Oxidation-Reduction, Pigments, Biological, Recombinant Proteins, Rats, Wistar, Rats, Cytochrome P-450 CYP2A6

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