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.

血小板活化因子(PAF)是一种具有生物活性的磷脂，对多种细胞如白细胞、平滑肌细胞、神经细胞等具有激活性，并与多种病理状态有关。乙醚磷脂氧化生成含有sn-2短链残基的衍生物，这些衍生物也具有类似PAF的生物活性。PAF乙酰水解酶(PAF-AH)使PAF或PAD样脂失活，并在血浆中发现高水平的活性。血浆PAF-AH缺乏症是由于该基因(G994T)的错义突变引起的，据报道，其在日本普通人群中的患病率约为4%。这种突变也是中风或缺血性心脏病的遗传危险因素。在本研究中，我们首次发现健康的习惯性吸烟者和不吸烟者的血浆PAF-AH缺乏症的患病率几乎相同。有高血压、糖尿病、高脂血症等血管疾病危险因素的人群(危险因素组)与无危险因素的人群(正常组)相比，突变基因的发生率无显著差异。然而，在正常基因型受试者中，危险因素组的PAF-AH活性高于正常组。在杂合基因的受试者中没有观察到这样的差异。其次，我们在吸烟后不久获得的血浆脂提取物中检测到一种聚集活性，并在薄层层析中与正品PAF共迁移。我们得出结论：在包括慢性生活方式疾病在内的各种疾病中，血浆PAF-AH作为一种过继机制而增加，该酶的缺乏可能与疾病风险的增加有关。

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.