Smoking-induced generation of oxidized phospholipids and the effect of deficiency of hydrolyzing enzyme for oxidatively modified phospholipids : role of the enzyme deficiency in carcinogenesis and vascular injury.

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Platelet-activating factor (PAF) is a bioactive phospholipid that has agonistic activities towards many types of cells such as white blood cells, smooth muscle cells, and neuronal cells ; and it is implicated various pathological conditions. Oxidation of ether phospholipids results in the generation of derivatives with a sn-2 short chain residue, and such derivatives also acquire PAF-like bioactivities. PAF or PAD-like lipids are inactivated by PAF acetylhydrolase (PAF-AH), and a high level of activity is found in plasma. Plasma PAF-AH deficiency is due to a missense mutation in the gene (G994T) and its prevalence among a general Japanese population is reported to be about 4%. This mutation is also known to be a genetic risk factor of stroke or ischemic heart disease.In the present study, we first found that the prevalence of plasma PAF-AH deficiency is virtually the same between healthy habitual smokers and non-smokers. There was no significant difference in the prevalence of the mutant gene between the group of the subjects who have risk factors for vascular diseases such as hypertension, diabetes mellitus, or hyperlipidemia (risk factor group) as compared to the group without such risk factors (normal group). However, among the subjects with normal genotype, the risk factor group had higher PAF-AH activity than the normal group. Such a difference was not observed for the subjects with the heterozygous genotype. Secondly, we detected an aggregating activity in lipid extracts of plasma obtained shortly after smoking cigarettes, and such activity co-migrated with authentic PAF in thin-layer chromatography.We conclude that plasma PAF-AH is increased in various diseases, including chronic lifestyle diseases, as an adoptive mechanism and the deficiency of this enzyme may be associated with enhanced risk for the diseases.