A high-level expression of CYP2A in the lung of the suncus (Suncus murinus) and its role in the activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone

Northern blot analysis of mRNA prepared from the lung of Suncus murinus (su ncus), which was classified as an ancestor of primates, revealed that the e xpression level of cytochrome P450 2A (CYP2A) mRNA was about 100-fold highe r than in the lung from rats and mice. To confirm that the pulmonary CYP2A of the suncus had a catalytic activity, the metabolism of a specific substr ate for CYP2A6, (+)-cis-3,5-dimethyl-2-(3-pyridyl) thiazolidin-4-one hydroc hloride (SM-12502), was determined. The intrinsic clearance for SM-12502 S- oxidation by the suncus lung microsomes was calculated to be 99-fold higher than that by rat liver microsomes. The mutagen-producing activity of a 900 0g supernatant fraction prepared from suncus lung was examined using 4-(met hylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as a promutagen. The results showed that the suncus lung possessed 82-fold higher mutagen-producing act ivity than the rat lung, indicating that NNK was efficiently activated by t he CYP2A isoform expressed in the suncus lung and that the suncus was a sen sitive animal species to the genotoxicity of NNK contained in tobacco smoke . (C) 2000 Academic Press.