Sohn Ock Soon, Desai Dhimant H, Das Arunangshu, Rodriguez Jose G, Amin Shantu G, El-Bayoumy Karam
Department of Biochemistry and Molecular Biology, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033-0850, USA.
Chem Biol Interact. 2005 Feb 10;151(3):193-202. doi: 10.1016/j.cbi.2004.10.007. Epub 2005 Jan 22.
In a previous preliminary investigation, we reported on the excretion, tissue disposition and metabolism of the chemopreventive agent 1,4-phenylenebis(methylene)selenocyanate (p-XSC) in the rat, but similar studies in the mouse have not been explored. Following the oral administration of p-XSC (50 micromol/kg body weight), selenium excretion in feces was comparable to that in urine in mice, but in rats, feces was the major route of excretion. Tetraselenocyclophane (TSC) was the major metabolite detected in mouse and rat feces. In both species, levels of selenium in exhaled air were negligible. At termination, in the mouse, the stomach had the highest selenium content followed by liver and blood, but lung and kidney contained negligible levels of selenium; in the rat, the selenium level in liver was the highest followed by kidney, stomach, blood and lung. The identification of TSC as a fecal metabolite in both species let us to postulate the following metabolic pathway: p-XSC-->glutathione conjugate (p-XSeSG)-->a selenol (p-XSeH)-->TSC. Since the glutathione conjugate appears to be the proximal precursor for the selenol metabolite that may be an important intermediate in cancer chemoprevention, we report for the first time the synthesis of p-XSeSG and its other potential metabolites, namely the cysteine- and N-acetylcysteine-conjugates of p-XSC. HPLC analysis of the urine and bile showed a few metabolites of p-XSC; none of which eluted with the synthetic standards described above. When we examined the conversion of p-XSC and p-XSeSG in vitro using rat cecal microflora, TSC was formed from p-XSeSG but not from p-XSC. The formation of TSC from p-XSC in vivo but not in vitro suggests that p-XSC needs to be metabolized to p-XSeSG or an intermediate derived from its further metabolism. Thus, p-XSeSG was given orally to rats and the results showed that the pattern of selenium excretion after p-XSeSG treatment was similar to that of p-XSC; TSC was also identified as a fecal metabolite of p-XSeSG. It may be that the conversion of p-XSeSG to TSC is too facile, or the mere conjugation of p-XSC with glutathione does not occur in rats and mice.
在之前的一项初步研究中，我们报道了化学预防剂1,4-亚苯基双（亚甲基）硒氰酸盐（p-XSC）在大鼠体内的排泄、组织分布和代谢情况，但尚未对小鼠进行类似研究。口服给予p-XSC（50微摩尔/千克体重）后，小鼠粪便中的硒排泄量与尿液中的相当，但在大鼠中，粪便则是主要的排泄途径。四硒环烷（TSC）是在小鼠和大鼠粪便中检测到的主要代谢产物。在这两个物种中，呼出气体中的硒含量可忽略不计。处死时，在小鼠中，胃中的硒含量最高，其次是肝脏和血液，但肺和肾脏中的硒含量可忽略不计；在大鼠中，肝脏中的硒水平最高，其次是肾脏、胃、血液和肺。在两个物种中均鉴定出TSC为粪便代谢产物，这使我们推测出以下代谢途径：p-XSC→谷胱甘肽共轭物（p-XSeSG）→硒醇（p-XSeH）→TSC。由于谷胱甘肽共轭物似乎是硒醇代谢产物的近端前体，而硒醇代谢产物可能是癌症化学预防中的重要中间体，我们首次报道了p-XSeSG及其其他潜在代谢产物的合成，即p-XSC的半胱氨酸和N-乙酰半胱氨酸共轭物。尿液和胆汁的HPLC分析显示了p-XSC的一些代谢产物；但没有一种与上述合成标准品的洗脱峰一致。当我们使用大鼠盲肠微生物群在体外研究p-XSC和p-XSeSG的转化时，TSC是由p-XSeSG形成的，而不是由p-XSC形成的。p-XSC在体内而非体外形成TSC，这表明p-XSC需要代谢为p-XSeSG或其进一步代谢产生的中间体。因此，给大鼠口服p-XSeSG，结果表明p-XSeSG处理后的硒排泄模式与p-XSC相似；TSC也被鉴定为p-XSeSG的粪便代谢产物。可能是p-XSeSG向TSC的转化过于容易，或者p-XSC与谷胱甘肽的共轭反应在大鼠和小鼠中根本不会发生。
