Nnane Ivo P, Damani Lyaquat A
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 N Broad Street, Philadelphia, PA 19140, USA.
Biomed Chromatogr. 2005 Jan;19(1):87-98. doi: 10.1002/bmc.421.
In this investigation, the measurement and identification of the S-oxidation products of three simple sulphides-ethyl methyl sulphide (EMS), 4-chlorophenyl methyl sulphide (CPMS) and diphenyl sulphide (DPS)-in rat urine were carried out and a study of the effects of phenobarbitone (PB), beta-naphtho flavone (betaNF) and methimazole on the urinary levels of their metabolites was conducted. Male Wistar rats (n = 4) were pretreated with PB (80 mg/kg/day in saline, i.p.), betaNF (100 mg/kg/day in corn oil, i.p.), methimazole (50 mg/kg/day in saline, i.p.) or the vehicles alone (1 mL/kg) for three consecutive days. After pretreatment, EMS, CPMS or DPS (50 mg/kg in corn oil, 500 microL) was administered orally to the appropriate groups of rats. The animals were placed in metabolic cages and urine samples collected at 24 h intervals over 96 h. Chromatographic and spectroscopic techniques were used for the measurement and identification of the sulphoxides and sulphones of EMS, CPMS and DPS in rat urine. Although only a trace of ethyl methyl sulphoxide (EMSO) was present in rat urine after administration of EMS, ethyl methyl sulphone (EMSO(2)) accounted for about 16% of the administered dose in the urine of male rats given EMS. In addition, pretreatment of rats with methimazole significantly decreased the S-oxidation of EMS. 4-Chlorophenyl methyl sulphone (CPMSO(2)) was the main metabolite recovered in the urine of male rats treated with CPMS, accounting for about 10% of the dose. Pretreatment of rats with PB before administration of CPMS significantly increased the levels of CPMSO(2) excreted in the urine. Additionally, pretreatment of rats with methimazole significantly decreased the S-oxidation of CPMS in vivo. About 2.5% of diphenyl sulphoxide (DPSO) and 4% of diphenyl sulphone (DPSO(2)) were recovered in the urine of male rats given DPS. Pretreatment of rats with PB, betaNF or methimazole before administration of DPS decreased the levels of DPSO and DPSO(2) excreted in the urine, although this was not statistically significant. These results indicate that microsomal monooxygenases mediate the S-oxidation of EMS, CPMS and DPS to their corresponding sulphones via a transient sulphoxide in rats.
在本研究中，对大鼠尿液中三种简单硫化物——甲乙硫醚（EMS）、4-氯苯甲硫醚（CPMS）和二苯硫醚（DPS）的S-氧化产物进行了测定和鉴定，并研究了苯巴比妥（PB）、β-萘黄酮（βNF）和甲巯咪唑对其代谢产物尿液水平的影响。雄性Wistar大鼠（n = 4）连续三天接受PB（80 mg/kg/天，溶于生理盐水，腹腔注射）、βNF（100 mg/kg/天，溶于玉米油，腹腔注射）、甲巯咪唑（50 mg/kg/天，溶于生理盐水，腹腔注射）或单独的赋形剂（1 mL/kg）预处理。预处理后，将EMS、CPMS或DPS（50 mg/kg，溶于玉米油，500 μL）经口给予相应组别的大鼠。将动物置于代谢笼中，在96小时内每隔24小时收集尿液样本。采用色谱和光谱技术对大鼠尿液中EMS、CPMS和DPS的亚砜和砜进行测定和鉴定。给予EMS后，大鼠尿液中仅存在微量的甲乙亚砜（EMSO），而甲乙砜（EMSO₂）在给予EMS的雄性大鼠尿液中占给药剂量的约16%。此外，用甲巯咪唑预处理大鼠可显著降低EMS的S-氧化。4-氯苯甲砜（CPMSO₂）是给予CPMS的雄性大鼠尿液中回收的主要代谢产物，约占剂量的10%。在给予CPMS前用PB预处理大鼠可显著增加尿液中排出的CPMSO₂水平。此外，用甲巯咪唑预处理大鼠可在体内显著降低CPMS 的S-氧化。给予DPS的雄性大鼠尿液中回收了约2.5%的二苯亚砜（DPSO）和4%的二苯砜（DPSO₂）。在给予DPS前用PB、βNF或甲巯咪唑预处理大鼠可降低尿液中排出的DPSO和DPSO₂水平，尽管这在统计学上无显著意义。这些结果表明，微粒体单加氧酶在大鼠体内通过短暂的亚砜将EMS、CPMS和DPS介导氧化为相应的砜。
