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Reduction in CYP1A1 and 2B2 activity at low oxygen tension
L Hernández-Gutiérrez1, R Camacho-Carranza1, S L Hernández-Ojeda1
1Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ap. Postal, 70-228 Ciudad de México, Mexico.
Toxicology Letters
|May 17, 2020
Summary
Low oxygen levels impair Cytochrome P450 (CYP) enzyme activity, reducing substrate oxidation efficiency. This study quanties the impact of hypoxia on CYP kinetics and xenobiotic metabolism.
Area of Science:
- Biochemistry
- Enzymology
- Pharmacology
Background:
- Cytochrome P450 (CYP) enzymes are crucial for metabolizing endogenous and exogenous compounds.
- CYP active sites feature an iron protoporphyrin center essential for oxygen activation during catalysis.
- Limited biochemical data exists on CYP kinetics under low oxygen conditions.
Purpose of the Study:
- To investigate the effect of varying oxygen concentrations on rat liver microsomal CYP enzyme kinetics.
- To assess the impact of hypoxia on the Vmax app and Km app of specific CYP isoforms.
- To evaluate the influence of low oxygen on the mutagenicity of known CYP substrates.
Main Methods:
- Measurement of Vmax app and Km app for resorufin production using alkoxyresorufin substrates in rat liver microsomes.
- Comparison of CYP kinetics under normal (6.5 ppm) and hypoxic (4.1 ppm) oxygen conditions.
- Assessment of bacterial mutagenicity for 2-aminoanthracene and cyclophosphamide under different oxygen levels.
Main Results:
- Vmax/Km ratios decreased for CYP1A1 (426 to 393) and CYP2B1 (343 to 202) at low oxygen concentrations.
- Bacterial mutagenicity of 2-aminoanthracene and cyclophosphamide reduced by 32% and 42%, respectively, under hypoxia.
- These findings indicate reduced substrate oxidation efficiency at lower oxygen availability.
Conclusions:
- Hypoxia significantly affects CYP enzyme kinetics, leading to decreased substrate oxidation.
- Low oxygen availability is implicated in the reduced efficiency of CYP-mediated xenobiotic metabolism.
- Further research is warranted to understand the full implications of hypoxia on drug metabolism and toxicity.
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