Yagen B, Foureman G L, Ben-Zvi Z, Ryan A J, Hernandez O, Cox R H, Bend J R
Drug Metab Dispos. 1984 Jul-Aug;12(4):389-95.
The metabolism and excretion of intramuscularly administered 14C-glutathione conjugates of styrene oxide (Ia and IIa) were studied in the winter flounder at three dose levels. The various radiolabeled thioether metabolites excreted were separated by reverse-phase high pressure liquid chromatography, and identified and quantitated by cochromatography with synthetic standards. The urine was the major excretion route for radioactivity derived from the glutathione conjugates (up to 90%) at each dose level (1.0, 3.9, and 24.4 mg/fish) studied. The corresponding cysteine derivatives (Ic, IIc) were the major urinary metabolites although the N-acetylcysteine derivatives (Id, IId), or mercapturic acids, were also present in significant amounts at each dose and excretion interval examined. Unchanged glutathione conjugates of styrene oxide were the major radioactive constituents of 24-hr bile samples from the treated flounder, although significant amounts of the cysteinylglycine (Ib, IIb), cysteine, and N-acetylcysteine derivatives were also present in bile. Bile was a minor excretory route relative to urine. The oxidation of 14C-styrene to styrene 7,8-oxide by the cytochrome P-450-dependent monooxygenase system of hepatic microsomes of winter flounder was also demonstrated; likewise, styrene was converted to the diastereomeric glutathione conjugates of styrene 7,8-oxide by 9,000g supernatant fractions of flounder liver supplemented with glutathione. This study demonstrated that flounder liver can convert styrene to glutathione conjugates to styrene oxide and that mercapturic acid biosynthesis occurs after parenteral administration of a xenobiotic-glutathione adduct to this marine species, although the major urinary metabolites were the cysteine conjugates rather than the anticipated mercapturic acid derivatives.
在三个剂量水平下，研究了冬季比目鱼体内肌内注射的氧化苯乙烯（Ia和IIa）的14C - 谷胱甘肽共轭物的代谢和排泄情况。通过反相高压液相色谱法分离排出的各种放射性硫醚代谢物，并通过与合成标准品共色谱法进行鉴定和定量。在所研究的每个剂量水平（1.0、3.9和24.4毫克/鱼）下，尿液是谷胱甘肽共轭物产生的放射性的主要排泄途径（高达90%）。相应的半胱氨酸衍生物（Ic、IIc）是主要的尿液代谢物，尽管在每个检查的剂量和排泄间隔中，N - 乙酰半胱氨酸衍生物（Id、IId）或巯基尿酸也大量存在。氧化苯乙烯的未变化谷胱甘肽共轭物是处理过的比目鱼24小时胆汁样本中的主要放射性成分，尽管胆汁中也存在大量的半胱氨酰甘氨酸（Ib、IIb）、半胱氨酸和N - 乙酰半胱氨酸衍生物。相对于尿液，胆汁是次要的排泄途径。还证明了冬季比目鱼肝微粒体的细胞色素P - 450依赖性单加氧酶系统可将14C - 苯乙烯氧化为苯乙烯7,8 - 氧化物；同样，在添加了谷胱甘肽的比目鱼肝9,000g上清液组分中，苯乙烯可转化为苯乙烯7,8 - 氧化物的非对映体谷胱甘肽共轭物。这项研究表明，比目鱼肝可以将苯乙烯转化为谷胱甘肽共轭物再到氧化苯乙烯，并且在向这种海洋物种肠胃外给药异源生物 - 谷胱甘肽加合物后会发生巯基尿酸生物合成，尽管主要的尿液代谢物是半胱氨酸共轭物而不是预期的巯基尿酸衍生物。
