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 (suncus), which was classified as an ancestor of primates, revealed that the expression level of cytochrome P450 2A (CYP2A) mRNA was about 100-fold higher 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 substrate for CYP2A6, (+)-cis-3,5-dimethyl-2-(3-pyridyl) thiazolidin-4-one hydrochloride (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 9,000 g supernatant fraction prepared from suncus lung was examined using 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as a promutagen. The results showed that the suncus lung possessed 82-fold higher mutagen-producing activity than the rat lung, indicating that NNK was efficiently activated by the CYP2A isoform expressed in the suncus lung and that the suncus was a sensitive animal species to the genotoxicity of NNK contained in tobacco smoke.
Mushiroda
T
T
Laboratory of Drug Metabolism, Division of Pharmacobio-dynamics, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, 060-0812, Japan.
Ariyoshi
N
N
Kimura
K
K
Takahara
E
E
Nagata
O
O
Kato
H
H
Kamataki
T
T
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics*; D002384:Catalysis; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D008168:Lung / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009602:Nitrosamines / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012788:Shrews; D013250:Steroid Hydroxylases / Q000378:metabolism*
D002273:Carcinogens; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C022657:steroid hormone 6-beta-hydroxylase