The biotransformation of a sulfonamide to a mercaptan and to mercapturic acid and glucuronide conjugates

Colucci, D; Buyske, D. A.

doi:10.1016/0006-2952(65)90218-2

Cited by 78 publications

(20 citation statements)

References 5 publications

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“…These results contrasted with those from control rats, which excreted 4.6% of the dose in the urine as naphthols and naphthol glucuronides. The absence of CH3S-metabolite was expected because many methylthio-containing metabolites of other xenobiotics are formed from biliary mercapturic acid pathway (MAP) metabolites by a process mediated by the intestinal microflora (8) and because the tissue cysteine conjugate j3-lyase system, which would be expected to mediate the formation of the CH3S-metabolite, exhibits a specificity for aromatic S-cysteine conjugates (9)(10)(11). Here, the substrate (I) is assumed to be present as a preMAP metabolite that does not exhibit the required aromaticity.…”

Section: Resultsmentioning

confidence: 99%

Catabolism of premercapturic acid pathway metabolites of naphthalene to naphthols and methylthio-containing metabolites in rats.

Bakke

Struble

Gustafsson

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

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ABSTRACT[14C]Naphthalene was given orally to rats with cannulated bile ducts and to germ-free rats, Bile and urine from the cannulated rats and urine from the germ-free rats contained no radioactive 1,2-dihydro-1-hydroxy-2-methylthionaphthalene and only trace amounts of radioactive naphthols or naphthol conjugates. Urine of control rats contained 4.6% of the 14C dose as naphthols and/or naphthol glucuronides. Appreciable quantities of 1-and 2-naphthol (7-20% of dose) and 1,2-dihydro-1-hydroxy-2-methylthionaphthalene (1-35% of dose) were in urine from rats dosed orally or intracecally with 1,2-dihydro-l-hydroxy-24S-cysteinylnaphthalene and 1,2-dihydro-1-hydroxy-2-S-(N-acetyl)cysteinylnaphthalene. Apparently, in vivo, naphthols and methylthio-containing metabolites of naphthalene are-formed during enterohepatic circulation of 1,2-dihydro-1-hydroxy-2-S-cysteinylnaphthalene and 1,2-dihydro-1-hydroxy-2-S-(N-acetyl)cysteinylnaphthalene in a process dependent upon intestinal microflora. A possible pathway for the formation of naphthols is aromatization of the precursor compounds by elimination of the appropriate substituent group from these metabolites. This discovery of the essential role of the intestinal microflora in the formation of naphthols from naphthalene indicates the existence of a novel pathway for hydroxylation of aromatic systems and challenges the current concept of the in vivo relevance of the in vitro production of naphthols from naphthalene 1,2-oxide.Hydroxylation of naphthalene is known to occur in vitro by nonenzymatic rearrangement of the 1,2-oxide intermediate (1) as outlined in Fig. 1. Although not directly stated, it is commonly inferred that this in vitro mechanism for formation of naphthols is operative in vivo. Here we present evidence from studies with rats that the 1,2-oxide is not the immediate precursor for the majority of the naphthols formed in vivo. We propose that most of the naphthols and the 1,2-dihydro-1-hydroxy-2-methylthionaphthalene (CH3S-metabolite) reported by Stillwell et al. (2) are formed during enterohepatic circulation of premercapturic acid pathway (pre-MAP, defined in Fig. 1) metabolites of naphthalene [1,2-dihydro-1-hydroxy-2-S-glutathionyl-, -cysteinylglycyl-, -cysteinyl-, and -(N-acetyl)cysteinylnaphthalene] by a process either mediated by the intestinal microflora or dependent upon their presence in the gut.EXPERIMENTAL PROCEDURES Chemicals. Naphthalene was obtained from Eastman Organic Chemicals, Rochester, NY. [1-14C]Naphthalene (5 mCi/mmol; 1 Ci = 37 GBq) was obtained from Amersham, 1-and 2-naphthol from Fisher, and 2-thionaphthol from Fluka. 1,2-Dihydro-1-hydroxy-2-S-cysteinyl[ C]naphthalene (I); 1,2-dihydro-1-hydroxy-2-S-(N-acetyl)cysteinyl[14C]naphthalene (II); and 1,2-dihydro-1,2-dihydroxy-[14C]naphthalene glucuronide (III) were isolated, as previously described (3), from bile (I) or urine (II and III) from rats during the period 0-24 hr after they were dosed orally with [1-'4C]naphthalene (2.0 mg/0.5 ACi in 0.5 ml of ethanol). I and II were assumed to have t...

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Section: Resultsmentioning

confidence: 99%

Catabolism of premercapturic acid pathway metabolites of naphthalene to naphthols and methylthio-containing metabolites in rats.

Bakke

Struble

Gustafsson

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

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“…From a structure-activity relationship perspective, a recurring structural theme in these examples is the presence of the methylsulfone/sulfonamide and/or halide leaving group, which is attached to an electron-deficient heteroaromatic ring system (e.g., pyridine, pyridone, benzothiazole, thiadiazole, benzofuran, indole, etc.) (Clapp, 1956;Colucci and Buyske, 1965;Conroy et al, 1984;Graham et al, 1989;Woltersdorf et al, 1989;Graham et al, 1990;Kishida et al, 1990;Huwe et al, 1991;Zhao et al, 1999;Teffera et al, 2008;Inoue et al, 2009;Litchfield et al, 2010). More recently, Yang et al (2012) have also demonstrated the susceptibility of 2-(alkylthio)-1,3,4-thiadiazoles and 2-(alkylthio)-1,3-benzothiazoles to undergo nucleophilic displacement with GSH in human liver microsomes.…”

Section: Discussionmentioning

confidence: 99%

Demonstration of the Innate Electrophilicity of 4-(3-(Benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP), a Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor

et al. 2013

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4-(3-(Benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP) represents a novel small-molecule activator of the glucagonlike peptide-1 receptor (GLP-1R), and exhibits glucose-dependent insulin secretion in rats following i.v. (but not oral) administration. To explore the quantitative pharmacology associated with GLP-1R agonism in preclinical species, the in vivo pharmacokinetics of BETP were examined in rats after i.v. and oral dosing. Failure to detect BETP in circulation after oral administration of a 10-mg/kg dose in rats was consistent with the lack of an insulinotropic effect of orally administered BETP in this species. Likewise, systemic concentrations of BETP in the rat upon i.v. administration (1 mg/kg) were minimal (and sporadic). In vitro incubations in bovine serum albumin, plasma, and liver microsomes from rodents and humans indicated a facile degradation of BETP. Failure to detect metabolites in plasma and liver microsomal incubations in the absence of NADP was suggestive of a covalent interaction between BETP and a protein amino acid residue(s) in these matrices. Incubations of BETP with glutathione (GSH) in buffer revealed a rapid nucleophilic displacement of the ethylsulfoxide functionality by GSH to yield adduct M1, which indicated that BETP was intrinsically electrophilic. The structure of M1 was unambiguously identified by comparison of its chromatographic and mass spectral properties with an authentic standard. The GSH conjugate of BETP was also characterized in NADPH-and GSH-supplemented liver microsomes and in plasma samples from the pharmacokinetic studies. Unlike BETP, M1 was inactive as an allosteric modulator of the GLP-1R.

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“…The outlined mechanism is certainly not beyond the realm of possibilities, considering the well-known chemical (and glutathione transferase-mediated) displacement reaction of GSH with electron-deficient heteroaromatic rings (e.g., pyridine, pyrimidine, etc.) that contain alkylsulfoxide and/or alkylsulfone as leaving groups (Clapp, 1956;Colucci and Buyske, 1965;Conroy et al, 1984;Graham et al, 1989;Yang et al, 2012). A literature example that bears much commonality to the present situation is evident with the proton pump inhibitor pantoprazole wherein the benzimidazole-2-sulfoxide motif undergoes nucleophilic attack by GSH at the electron-deficient C2 position on the benzimidazole ring (Zhong et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Reactive Metabolite Trapping Studies on Imidazo- and 2-Methylimidazo[2,1-b]thiazole-Based Inverse Agonists of the Ghrelin Receptor

et al. 2013

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The current study examined the bioactivation potential of ghrelin receptor inverse agonists, 1-{2-[2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl]-2,7-diazaspiro[3.5]nonan-7-yl}-2-(imidazo[2,1-b]thiazol-6-yl)ethanone (1) and 1-{2-[2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl]-2,7-diazaspiro[3.5]nonan-7-yl}-2-(2-methylimidazo[2,1-b]thiazol-6-yl) ethanone (2), containing a fused imidazo[2,1-b]thiazole motif in the core structure. Both compounds underwent oxidative metabolism in NADPH-and glutathione-supplemented human liver microsomes to yield glutathione conjugates, which was consistent with their bioactivation to reactive species. Mass spectral fragmentation and NMR analysis indicated that the site of attachment of the glutathionyl moiety in the thiol conjugates was on the thiazole ring within the bicycle. Two glutathione conjugates were discerned with the imidazo[2,1-b]thiazole derivative 1. One adduct was derived from the Michael addition of glutathione to a putative S-oxide metabolite of 1, whereas, the second adduct was formed via the reaction of a second glutathione molecule with the initial glutathione-S-oxide adduct. In the case of the 2-methylimidazo[2,1-b]thiazole analog 2, glutathione conjugation occurred via an oxidative desulfation mechanism, possibly involving thiazole ring epoxidation as the rate-limiting step. Additional insights into the mechanism were obtained via 18 O exchange and trapping studies with potassium cyanide. The mechanistic insights into the bioactivation pathways of 1 and 2 allowed the deployment of a rational chemical intervention strategy that involved replacement of the thiazole ring with a 1,2,4-thiadiazole group to yield 2-,4]thiadiazol-6-yl)ethanone (3). These structural changes not only abrogated the bioactivation liability but also retained the attractive pharmacological attributes of the prototype agents.

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The biotransformation of a sulfonamide to a mercaptan and to mercapturic acid and glucuronide conjugates

Cited by 78 publications

References 5 publications

Catabolism of premercapturic acid pathway metabolites of naphthalene to naphthols and methylthio-containing metabolites in rats.

Catabolism of premercapturic acid pathway metabolites of naphthalene to naphthols and methylthio-containing metabolites in rats.

Demonstration of the Innate Electrophilicity of 4-(3-(Benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP), a Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor

Reactive Metabolite Trapping Studies on Imidazo- and 2-Methylimidazo[2,1-b]thiazole-Based Inverse Agonists of the Ghrelin Receptor

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