Metabolic activation of saturated aldehydes to cause destruction of cytochrome P-450 in vitro.
The results of this paper demonstrate for the first time that a number of saturated aliphatic aldehydes, e.g. octanal, when incubated with rat liver microsomes and NADPH in vitro cause the time dependent destruction of cytochrome P-450 and the formation of green pigments. No loss of this cytochrome occurred when microsomes were incubated with aldehydes in the absence of NADPH. The activating enzymes had some characteristics typical of the microsomal mixed-function oxidases. Formaldehyde and acetaldehyde did not appear to be activated by this system. Octanal had no effect on hepatic microsomal cytochrome P-450 when administered to rats (1 mmol/kg, i.p.) in vivo. Under similar conditions, the ethynyl-substituted 1-octyne caused a significant destruction of this cytochrome. In order to prelabel liver haem with 14C, rats were pretreated with 5-amino[4-14C]laevulinic acid. Microsomal fractions prepared from these animals were incubated with octanal. Destruction of cytochrome P-450 was accompanied by the appearance of 14C-labelled green pigments separated by HPLC. The properties of the green pigments produced by incubating microsomes with either octanal or 1-ocytne have been compared. From their chromatographic behaviour and spectrophotometrically they appear to be similar though not identical. The results suggest that octanal induced green pigments may contain chelated iron which is not readily removed. The possibility that aldehyde could be metabolically activated via a ketene intermediate was investigated. Although attempts to prepare the ketene analogue of octanal were not successful, ketene gas, prepared chemically, reacted with haem in chloroform and to a limited extent with aqueous microsomal suspensions. However, the reaction products were brown in colour and gave an absorption spectrum indistinguishable from that of haem. There was no evidence of green pigment formation.[1]References
- Metabolic activation of saturated aldehydes to cause destruction of cytochrome P-450 in vitro. White, I.N. Chem. Biol. Interact. (1982) [Pubmed]
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