Israels L G, Israels E D
Department of Medicine, University of Manitoba, Manitoba Institute of Cell Biology, Winnipeg, Canada.
Semin Thromb Hemost. 1995;21(4):357-63. doi: 10.1055/s-2007-1000656.
The microsomal mixed function oxidase system metabolizes xenobiotics (Phase I) to products that, if not activated and conjugated for excretion (Phase II), are capable of forming conjugates with cellular macromolecules, including DNA, resulting in toxic, mutagenic, or carcinogenic events. Benzo(a)pyrene (BP), a polycyclic aromatic hydrocarbon, is a model carcinogen for this system. Vitamin K1 (phylloquinone) is a regulator of BP metabolism. These studies demonstrate that K1 is capable of increasing Phase I metabolism and decreasing glutathione transferase activity (Phase II) in chick embryo liver; that deprivation of K1 reduces BP/DNA adducts in mouse liver and reduces tumor formation in mice given intraperitoneal BP; and that K1 supplementation increases BP induced tumor formation in mice. However, epidemiologic studies indicate that children of mothers who smoke during pregnancy may not be at increased risk of cancer. It is known that the placentas from these pregnancies exhibit markedly increased levels of arylhydrocarbon hydroxylase induced by the polycyclic aromatic hydrocarbons in tobacco smoke, but there is no corresponding increase in this enzyme activity in the fetus in such pregnancies. We suggest that the low vitamin K level is a secondary protective mechanism for xenobiotics, such as BP, that may escape the primary placental screen. The recently described role of vitamin K-dependent Gla protein as ligands for receptor tyrosine kinases, also establishes K as a link in cell growth and transformation. It is proposed that the small total body pool of K1 in the adult, which is sufficient only to meet continuing needs, and the even smaller pool in the fetus are protective. This protective effect of low K1 levels is particularly important in the presence of the high mitotic rates and rapid cell turnover in the avian embryo and mammalian fetus.
微粒体混合功能氧化酶系统将外源性物质（I相）代谢为产物，这些产物如果不被激活并结合以便排泄（II相），就能够与包括DNA在内的细胞大分子形成结合物，从而导致毒性、致突变或致癌事件。苯并(a)芘（BP）是一种多环芳烃，是该系统的典型致癌物。维生素K1（叶绿醌）是BP代谢的调节剂。这些研究表明，K1能够增加鸡胚肝脏中的I相代谢并降低谷胱甘肽转移酶活性（II相）；K1缺乏会减少小鼠肝脏中的BP/DNA加合物，并减少腹腔注射BP的小鼠中的肿瘤形成；而补充K1会增加BP诱导的小鼠肿瘤形成。然而，流行病学研究表明，孕期吸烟母亲的孩子患癌症的风险可能不会增加。已知这些孕期的胎盘表现出由烟草烟雾中的多环芳烃诱导的芳烃羟化酶水平显著升高，但此类孕期胎儿中的这种酶活性并无相应增加。我们认为低维生素K水平是外源性物质（如BP）的一种次要保护机制，这些外源性物质可能逃避胎盘的主要筛选。最近描述的维生素K依赖的Gla蛋白作为受体酪氨酸激酶配体的作用，也确立了K在细胞生长和转化中的联系。有人提出，成年人中K1的全身总量小，仅足以满足持续需求，而胎儿中的总量更小，这具有保护作用。在禽类胚胎和哺乳动物胎儿有高有丝分裂率和快速细胞更新的情况下，低K1水平的这种保护作用尤为重要。
