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Lookup NU author(s): Professor William Watson, Dr Tony Munter, Emeritus Professor Bernard Golding
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2023 The Authors/ Vitamin B12 (cyano- or hydroxo-cobalamin) acts, via its coenzymes, methyl- and adenosyl-cobalamin, as a partner for enzymatic reactions in humans catalysed by methionine synthase and methylmalonyl-CoA mutase. As well as its association with pernicious anaemia, human B12 deficiency may also be a risk factor for neurological illnesses, heart disease and cancer. In the present work the effect of vitamin B12 (hydroxocobalamin) on the formation of DNA adducts by the epoxide phenyloxirane (styrene oxide), a genotoxic metabolite of phenylethene (styrene), has been studied using an in vitro model system. Styrene was converted to its major metabolite styrene oxide as a mixture of enantiomers using a microsomal fraction from the livers of Sprague-Dawley rats with concomitant inhibition of epoxide hydrolase. However, microsomal oxidation of styrene in the presence of vitamin B12 gave diastereoisomeric 2-hydroxy-2-phenylcobalamins. The quantitative formation of styrene oxide-DNA adducts was investigated using 2-deoxyguanosine or calf thymus DNA in the presence or absence of vitamin B12. Microsomal incubations containing either deoxyguanosine or DNA in the absence of vitamin B12 gave 2-amino-7-(2-hydroxy-1-phenylethyl)-1,7-dihydro-6H-purin-6-one [N7-(2-hydroxy-1-phenylethyl)-guanine], and 2-amino-7-(2-hydroxy-2-phenylethyl)-1,7-dihydro-6H-purin-6-one [N7-(2-hydroxy-2-phenylethyl)guanine] as the principal adducts. With deoxyguanosine the level of formation of guanine adducts was ca. 150 adducts/106 unmodified nucleoside. With DNA the adduct level was 36 pmol/mg DNA (ca. 1 adduct/0.83 × 105 nucleotides). Styrene oxide adducts from deoxyguanosine or DNA were not detected in microsomal incubations of styrene in the presence of vitamin B12. These results suggest that vitamin B12 could protect DNA against genotoxicity due to styrene oxide and other xenobiotic metabolites. However, this potential defence mechanism requires that the 2-hydroxyalkylcobalamins derived from epoxides are not ‘anti-vitamins’ and ideally liberate, and therefore, recycle vitamin B12. Otherwise, depletion of vitamin B12 leading to human deficiency could increase the risk of carcinogenesis initiated by genotoxic epoxides.
Author(s): Watson WP, Munter T, Golding BT
Publication type: Article
Publication status: Published
Journal: Chemico-Biological Interactions
Year: 2023
Volume: 382
Print publication date: 01/09/2023
Online publication date: 09/06/2023
Acceptance date: 31/05/2023
Date deposited: 03/07/2023
ISSN (print): 0009-2797
ISSN (electronic): 1872-7786
Publisher: Elsevier Ireland Ltd
URL: https://doi.org/10.1016/j.cbi.2023.110591
DOI: 10.1016/j.cbi.2023.110591
PubMed id: 37302460
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