Methyl sulfide, metabolites

The DDT metabolites, 4,4 -DDE (l,l-bis(4-chlorophenyl)-2,2-dichloro-ethene) and 2,4 -DDE are OHS that form MeS02-containing metabolites that persist in biota and humans [4,11,12,15,22,23]. Of particular concern is 3-MeS02-4,4 -DDE which is bioactivated to a reactive metabolite that irreversibly binds in the adrenal cortex of some species [24-27]. CYP1 If hydroxylase activity is perturbed in several species, and thus interference with glucocorticoid synthesis in vivo is possible. Hexachlorobenzene (HCB) is a major OHS that forms HCB methyl sulfide metabolites in HCB-exposed rats [28,29]. However,... 

Recently, Germain et al. (90) studied the in vivo metabolism of diallyl disulfide (DADS), a garlic compound claimed to have anticarcinogenic effects. After oral administration of a single dose of 200mg/kg, metabolites were measured in the stomach, liver, plasma, and urine by GC coupled with MS over 15 days. DADS was detected in almost all analyzed tissues within the first hours. In addition, the metabolites allylmercaptan (AM) and allyl methyl sulfide (AMS) were detected. The Cmav of the metabolites were higher than that of DADS (1.46 pg/mL). The %ax for DADS was estimated to be less than one hour, whereas this time increased to 24 hours for AM and AMS (90). 

Tsuchihashi et al. (1998) have developed a method for identification of VX metabolites in serum collected from a victim of the Osaka VX incident. In the serum sample, both EMPA and 2-(diisopropylamino-ethyl)methyl sulfide were detected. The techniques using GC-MS and GC-MS-MS were applicable to biological samples such as serum. These results provided the first documented identification of the specific metabolites of VX in victims serum and clarified a part of the metabolic pathway of VX in the human body. In addition, methods have been developed for measuring the VX-inhibited AChE hydrolytic product EMPA (Noort et al, 1998 2002). 

Synthesis of Methyl Sulfide, Sulfoxide and Sulfone Metabolites of... 

The further degradation of MAP metabolites to methyl sulfides and their oxidized products have been reported for many exogenous compounds (212). Animal tissues and gut microflora contain C-S lyase activity that Is responsible for the formation of thiols from GSH and related conjugates (213,214). These thiols may be methylated and subsequently oxidized to the corresponding sulfoxides and sulfones. 

Synthesis of these simple type of thiol derivatives will be Just briefly discussed here because comprehensive reviews on thiols and their derivatives are available (2, 21 ). The methyl sulfide compounds are most readily obtained by methylation of the corresponding thiol. Nucleophilic substitutions with methane thlolate on alkyl halides and occasionally with aryl halides lead directly to the methyl sulfide product. The syntheses of methyl sulfide and sulfone metabolites of xenoblotlca are summarized In Table IX. 

Allyl mercaptan and allyl methyl sulfide were identified as metabolites of diallyl disulfide when primary rat hepatocytes were incubated with either diallyl disulfide or diallyl sulfide. The highest identified concentration of allyl methyl sulfide (0.93 0.08 pg/ml at 90 min) was markedly lower than that of allyl mercaptan (46.2 6.6 pg/ml at 60 min). The results also showed that allyl methyl sulfide is a metabolite of diallyl sulfide (Sheen et al., 1999). 

Chemical warfare nerve agents pose a potential threat to the general public as well as the military, as evidenced by several incidents. Between 1980 and 1988, sarin (GB) was used by Iraq in the war with Iran, with the most notable incident occurring in 1988 when a Kurdish city in northern Iraq was bombarded with chemicals, possibly including GB, tabun (GA) and 0-ethyl 5-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX). In 1994 and 1995, the Aum Shinrikyo sect attacked subways in Matsumoto and Tokyo with GB, and also attacked individuals with VX in Osaka and Tokyo. One of these individual attacks resulted in the death of the intended victim. The victim had VX deposited on his neck and exhibited symptoms typical of organo-phosphate poisoning, but confirmation of the nerve agent used could only be achieved after his death with the testimony from one of the suspected attackers and detection of VX metabolites [ethyl methylphosphonic acid (EMPA) and 2-(diisopropylamino-ethyl)methyl sulfide (DAEMS)] in a blood sample taken approximately 1 h after the attack. 

Soil. Soil metabolites include formaldehyde, hydrogen sulfide, methylamine, and methyl(methylaminomethyl)dithiocarbamic acid (Hartley and Kidd, 1987), the latter decomposing to methyl isothiocyanate (Ashton and Monaco, 1991 Hartley and Kidd, 1987 Cremlyn, 1991). The rate of decomposition is dependent upon the soil type, temperature, and humidity (Cremlyn, 1991). 

Amantea and Narang [58] used a reversed-phase HPLC method for the quantitation of omeprazole and its metabolites. Plasma was mixed with the internal standard (the 5-methyl analog of omeprazole), dichlor-omethane, hexane, and 0.1 M carbonate buffer (pH 9.8). After centrifugation, the organic phase was evaporated to dryness and the residue was dissolved in the mobile phase [methanol-acetonitrile-0.025 M phosphate buffer of pH 7.4 (10 2 13)] and subjected to HPLC at 25 °C on a column (15 cm x 4.6 mm) of Beckman Ultrasphere C8 (5 ym) with a guard column (7 cm x 2.2 mm) of Pell C8 (30-40 /im). The mobile phase flow-rate was 1.1 ml/min with detection at 302 nm. The calibration graphs are linear for <200 ng/ml, and the limits of detection were 5, 10, and 7.5 ng/ml for omeprazole, its sulfone, and its sulfide, respectively. The corresponding recoveries were 96.42% and 96% and the coefficients of variation (n = 5 or 6) were 3.0-13.9%. 

VX appears to follow a similar pathway, the major metabolite being ethyl MPA (EMPA). An additional metabolite, derived from the diisopropy-laminoethyl substituent, was identified in human plasma following an assassination with VX (45). The sulfide (17), derived from enzymatic S-methylation of the hydrolysis product HSCH2CH2N(i-Pr)2, was identified in human serum by GC/MS after simple extraction. Experiments in rats confirmed the rapid metabolic formation of (17) from HSCH2CH2N(i-Pr)2 (46). Identification of this metabolite distinguishes VX from the O-ethyl analogue of sarin. 

OSHA PEL TWA 0.01 mg(As)/m3 ACGIH TLV TLV 0.01 mg/m Confirmed Human Carcinogen BEI 35 n (As)/L inorganic arsenic and methylated metabolites in urine NIOSH REL CL 2 ng(As)/mVl5M SAFETY PROFILE Confirmed human carcinogen. See also ARSENIC COMPOUNDS and SULFIDES. Flammable in the form of dust when exposed to heat or flame. Explosive when intimately mixed with powerful oxidizers, such as CI2, KNO3, or chlorates. Will react with water and steam to produce toxic and flammable vapors. Incompatible with water, steam, and strong oxidizers. 

Sulindac sulfide, the bioactive metabolite of sulindac, is struchirally very similar to INDO and is a slow, tight-binding inhibitor of COX (Fig. 2b) (12, 13). As with INDO, removal of the methyl group from sulindac sulfide results in loss of COX-1 and COX-2 inhibition (14). However, it should be noted that the benzylidine double bond of rfei-methyl sulindac sulfide (DM-SS) exists in the F-conformation, whereas sulindac sulfide exists in the Z-conformer. 

The active substance is not toxic to mammals, the acute oral ld,o for male rats is 4900 mg/kg. The active substance is rapidly absorbed and metabolised in the animal. It is excreted in the urine and feces, llie following metabolites have been detected in the urine p-(l,l-dimethyl-2-hydroxyethyl)benzylmethyl sulfide and sulfone, and p-(l-methyl-l-carboxyethyI)benzyImethyl sulfide and sulfone and their glucuronide conjugates. In addition to these, butyl-(l,I-dimethyl-2-hydroxyethyl)benzyl-N-(3-pyridyl)dithiocarbonimidate has been detected in the feces (Ohkawa et al., 1975). 

Methyl-substituted cyclic sulfides can be expected to undergo oxidation by cytochrome P450 enzymes to produce the corresponding sulfoxides (Takata et al., 1983). The mono-sulfoxides are predicted to be the main urinary metabolites of simple cyclic sulfides. 

Although they are more stable than hydrates, simple geminal dithiols (Nos 1660 and 1661) can undergo hydrolysis to yield their parent aldehydes and to release hydrogen sulfide (Mayer et al., 1963). The metabolism of the other simple aliphatic dithiol (No. 1709) is predicted to involve the pathways described above for simple thiols. Urinary metabolites could result from methylation, S-oxidation of a sulfur atom to yield a polar sulfonate and the formation of mixed disulfides by combination with a low molecular weight endogenous thiol such as cysteine. 

Radiolabelled metabolites were identified in the urine, carcass and intestines of mice after the administration of a single subcutaneous 10 mg dose of S-labelled diethyl disulfide (approximately 400 mg/kg bw) in an aqueous vehicle. Ethyl methyl sulfone was detected in the urine, carcass and intestines of mice after a single oral dose of 160 mg diethyl disulfide/kg bw. This product forms via reduction of diethyl disulfide to ethyl thiol, which is subsequently methylated to methyl ethyl sulfide. The sulfide is then oxidized to the corresponding sulfone. Sulfate accounted for 80-90% of the radioactivity in urine. Ethyl methyl sulfone was also detected in the urine of rabbits and guinea-pigs after single oral doses of 200 and 185 mg diethyl disulfide/ kg bw, respeotively (Snow, 1957). 

Although some oxidation of biotin to form biotin sulfoxides had been noted,and the sulfones of biotin and bisnorbiotin were isolated from cultures of the bacteria grown on the d-sulfoxide, growth experiments indicated that the thiolanyl S must be at the level of sulfide to be extirpated. As with lipoate, details of the metabolic events that lead to release of S fragments are lacking however, we have recently isolated methyl thioacetate as a volatile metabolite. 

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