Peroxidase-like activity of uncoupled cytochrome P450: studies with bilirubin and toxicological implications of uncoupling

Biochemical Pharmacology
F De MatteisDonovan C Haines

Abstract

The NADPH-dependent consumption of O(2) by cytochrome P450 BM3 was stimulated by either laurate or perfluorolaurate, but the NADPH/O(2) molar consumption ratios were approximately 1 and 2, respectively, indicating that perfluorolaurate does not become oxygenated by BM3 and oxygen undergoes full reduction to water. The nature of this catalytic cycle uncoupled to hydroxylation was explored using bilirubin as a molecular probe. During uncoupling with perfluorolaurate bilirubin was degraded and stimulated O(2) uptake by an approximately equimolar amount. No stimulation of oxygen uptake was caused by bilirubin in presence of NADPH alone or in presence of laurate together with NADPH; under these conditions little degradation of bilirubin was observed. Mesobilirubin was also degraded during uncoupling with perfluorolaurate, whereas biliverdin (which lacks the central methene bridge present in rubins) was unaffected. It is suggested that the CYP ferryl oxygen species abstracts a hydrogen atom from the central methene bridge of bilirubin to generate a radical, which is further dehydrogenated to biliverdin or else binds O(2) and undergoes fragmentation. We conclude that the uncoupled catalytic cycle of cytochrome P450 has properties rese...Continue Reading

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Feb 18, 2016·Toxicological Sciences : an Official Journal of the Society of Toxicology·John T SzilagyiJeffrey D Laskin
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Jun 5, 2015·Chemical Research in Toxicology·Ekaterina A Korobkova

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