The Metabolic Formation of Mercapturic Acids from Allyl Halides

Kaye, C M; Clapp, J J; Young, L.

doi:10.3109/00498257209111044

Cited by 43 publications

(12 citation statements)

References 19 publications

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“…The formation of SACS from SAC has been previously suggested, based upon the use of paper chromatography (Kaye et al, 1972). Our results provide further evidence for SAC sulfoxidation.…”

Section: Discussionsupporting

confidence: 74%

“…SAC is also a known metabolite of allyl halides and allyl esters, including allyl chloride, allyl bromide, sodium allyl sulfate, and allyl nitrate (Kaye et al, 1972;Kaye, 1973). It results from the formation of the glutathione conjugate of the allyl halide or ester.…”

Section: S-allyl-l-cysteinementioning

confidence: 99%

“…NASAC is an expected metabolite because it has been detected in the urine of rats, mice, and dogs dosed with SAC (Kaye et al, 1972;Nagae et al, 1994) and in the urine of humans who consumed garlic (de Rooij et al, 1996). The studies by Kaye and coworkers (Kaye et al, 1972;Kaye, 1973) used paper chromatography to suggest the formation of NASACS in rats given allyl chloride, allyl bromide, allyl iodide, triallyl phosphate, sodium allyl sulfate, or allyl nitrate, but no quantitation of NASACS formation was provided and to date, no study has examined the role of FMOs in SAC metabolism in vivo. Thus, the purpose of the current study was to characterize and quantify the major metabolites formed from SAC in vivo, especially those that are due to sulfoxidation by the FMOs, and to determine whether addition of the N-acetyl moiety affects SAC's ability to be oxidized by rat liver microsomes.…”

mentioning

confidence: 99%

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Sulfoxides as Urinary Metabolites ofS-Allyl-l-Cysteine in Rats: Evidence for the Involvement of Flavin-Containing Monooxygenases

Krause¹,

Glocke²,

Elfarra³

2002

Drug Metab Dispos

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ABSTRACT:S-Allyl-L-cysteine (SAC), a component of garlic and a metabolite of allyl halides, is a known substrate for multiple flavin-containing monooxygenases (FMOs). In the current study, we characterize the in vivo SAC metabolism by investigating the presence of SAC, N-acetyl-S-allyl-L-cysteine (NASAC), and their corresponding sulfoxides in the urine of rats given SAC (200 or 400 mg/kg i.p.). In some experiments, rats were given aminooxyacetic acid (AOAA), an inhibitor of cysteine conjugate ␤-lyase, or methimazole, an alternative FMO substrate, 30 min prior to treatment with 200 mg/kg SAC. Nearly 40 to 50% of the dose was recovered in the 24-h collection period. In all treatment groups, the majority of the metabolites were excreted within 8 h. The major metabolites detected were NASAC and NASAC sulfoxide (NASACS; nearly 30-40% and 5-10% of the dose, respectively). Only small amounts of the dose (approximately 1.5%) were recovered as SAC and SAC sulfoxide (SACS). Methimazole pretreatment significantly reduced amounts of both SACS and NASACS detected in the urine when compared with rats given SAC only, whereas AOAA pretreatment had no effect. In vitro assays using rat liver microsomes were also carried out to compare the sulfoxidation rates of SAC and NASAC. The results showed that SAC was much more readily oxidized than NASAC. Collectively, the results provide evidence for the involvement of FMOs in the in vivo metabolism of SAC and that SAC is a much better substrate for FMOs than its corresponding mercapturic acid. (SAC 1 ) is a significant water-soluble allyl sulfur component in garlic preparations (Weinberg et al., 1993), a component which has been shown to have antioxidant and anticancer properties in animals (Sumiyoshi and Wargovich, 1990;Hatono et al., 1996;Ho et al., 2001). SAC has been shown to have antiproliferative effects on neuroblastoma (Welch et al., 1992), melanoma (Takeyama et al., 1993), and prostate carcinoma cells (Pinto et al., 1997). However, the mechanisms of the anticancer properties of SAC are unclear. S-Allyl-L-cysteineSAC is also a known metabolite of allyl halides and allyl esters, including allyl chloride, allyl bromide, sodium allyl sulfate, and allyl nitrate (Kaye et al., 1972;Kaye, 1973). It results from the formation of the glutathione conjugate of the allyl halide or ester. The glutamate and glycine moieties of S-allyl-glutathione are then cleaved by ␥-glutamyl transpeptidase and dipeptidases to yield SAC.Our laboratory has previously shown that SAC is a substrate for multiple rabbit and human flavin-containing monooxygenases (FMOs). FMOs are microsomal enzymes that catalyze the NADPHdependent oxidation of many compounds that contain sulfur, nitrogen, selenium, and phosphorus (Ziegler, 1993). Previously, we have shown that SAC is metabolized to the greatest extent by cDNA-expressed rabbit FMO3 followed by FMO1 and then FMO2, but SAC showed no activity with rabbit FMO5 (Ripp et al., 1997). More recently and using cDNA-expressed human FMOs, SAC has been shown to be a good substr...

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“…The formation of SACS from SAC has been previously suggested, based upon the use of paper chromatography (Kaye et al, 1972). Our results provide further evidence for SAC sulfoxidation.…”

Section: Discussionsupporting

confidence: 74%

Section: S-allyl-l-cysteinementioning

confidence: 99%

mentioning

confidence: 99%

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Sulfoxides as Urinary Metabolites ofS-Allyl-l-Cysteine in Rats: Evidence for the Involvement of Flavin-Containing Monooxygenases

Krause¹,

Glocke²,

Elfarra³

2002

Drug Metab Dispos

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show abstract

“…S-Allyl-L-cysteine (SAC) is a component of garlic and a known metabolite of allyl halides (Kaye et al, 1972). SAC has antioxidant properties and antiproliferative effects on melanoma and prostate carcinoma cells (Hatano et al, 1996;Ho et al, 2001;Takeyama et al, 1993;Pinto et al, 1997).…”

mentioning

confidence: 99%

Human Kidney Flavin-Containing Monooxygenases and Their Potential Roles in CysteineS-Conjugate Metabolism and Nephrotoxicity

Krause¹,

Lash²,

Elfarra³

2003

J Pharmacol Exp Ther

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The potential roles of human hepatic and renal flavin-containing monooxygenases (FMOs) in the metabolism of the cysteine S-conjugates S-allyl cysteine (SAC) and S-(1,2-dichlorovinyl)-L-cysteine (DCVC) were investigated. Incubations of human cDNA-expressed FMO1, FMO3, FMO4, and FMO5 with SAC resulted in detection of SAC sulfoxide, with FMO3 exhibiting approximately 3-, 4-, and 10-fold higher activity than FMO1, FMO4, and FMO5, respectively. DCVC sulfoxide formation was only detected with FMO3 and was 59-fold lower than SAC sulfoxide formation. Incubations of human liver microsomes with SAC or DCVC resulted in detection of the corresponding sulfoxides and provided evidence for the involvement of FMO3. Incubations of SAC or DCVC with human kidney microsomes, however, led only to the detection of SAC sulfoxide. Immunoblots with monospecific antibodies to FMO1, FMO3, and FMO5 in kidney microsomes from 26 humans showed that the average expression levels for FMO1, FMO3, and FMO5 were 5.8 Ϯ 2.3, 0.5 Ϯ 0.4, and 2.4 Ϯ 1.4 pmol/mg (means Ϯ S.D.), respectively. Interestingly, African-American kidney samples (n ϭ 8) exhibited significantly higher FMO1 levels than Caucasian samples (n ϭ 17), whereas no difference in expression level between males and females was observed with any of the examined FMO isoforms. Collectively, the results provide evidence for the expression of three FMO isoforms in the human kidney and show that the contribution of renal FMOs in cysteine Sconjugate metabolism is likely to vary depending upon the cysteine S-conjugate and the relative expression levels of the active FMOs.Flavin-containing monooxygenases (FMOs) are microsomal enzymes that catalyze oxidation of sulfur-, selenium-, and nitrogen-containing compounds (Ziegler, 1993). Five active isoforms have been identified and are present in most mammalian tissues. However, species-, sex-, tissue-, and agedependent differences exist in expression levels of these isoforms (Hines et al., 1994;Dolphin et al., 1996;

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“…This toxicity results from conversion to allyl alcohol and subsequent formation of the toxic intermediate acrolein. A number of studies have focused on the metabolism and toxicity of allylic compounds, notably acrolein [2], allyl alcohol [3], allylamine [4], allyl halides [5], allyl cyanide [6], and allyl formate [1] (for a review see [7]), many of which have been found not only in industrial environments, but also in environmental pollutants, such as tobacco smoke. The biochemical analyses performed in these studies indicated that the major metabolic products are 3-hydroxypropylmercapturic acid (HPMA) and 2-carboxyethylmercapturic acid (CEMA), end products of the detoxification of acrolein via glutathione (GSH) conjugation ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Quantitative urinalysis of the mercapturic acid conjugates of allyl formate using high-resolution NMR spectroscopy

Athersuch¹,

Keun²,

Tang³

et al. 2006

Journal of Pharmaceutical and Biomedical Analysis

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The Metabolic Formation of Mercapturic Acids from Allyl Halides

Cited by 43 publications

References 19 publications

Sulfoxides as Urinary Metabolites ofS-Allyl-l-Cysteine in Rats: Evidence for the Involvement of Flavin-Containing Monooxygenases

Sulfoxides as Urinary Metabolites ofS-Allyl-l-Cysteine in Rats: Evidence for the Involvement of Flavin-Containing Monooxygenases

Human Kidney Flavin-Containing Monooxygenases and Their Potential Roles in CysteineS-Conjugate Metabolism and Nephrotoxicity

Quantitative urinalysis of the mercapturic acid conjugates of allyl formate using high-resolution NMR spectroscopy

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