Identification of N-Acetylcysteine Conjugates of 1,2-Dibromo-3-chloropropane: Evidence for Cytochrome P450 and Glutathione Mediated Bioactivation Pathways

Weber, Gregory L.; Steenwyk, Rick C.; Nelson, Sidney D.; Pearson, Paul G.

doi:10.1021/tx00046a010

Cited by 19 publications

(9 citation statements)

References 24 publications

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“…Evidence for the importance of this sequential pathway comes from studies that showed a substantial deuterium isotope effect (ϳ8) for perdeuterated Tris-BP on the clastogenicity of this compound in rat liver (Van Beerendonk et al, 1994), and a similar isotope effect was observed on the formation of GSH conjugates of oxidized Tris-BP metabolites (Van Beerendonk et al, 1995). Studies with DBCP showed the formation of several mercapturic acid conjugates of oxidative metabolites of DBCP that formed alternate products with selectively deuterated analogs of DBCP, most likely as a result of isotopically sensitive branching in the oxidation step (Weber et al, 1995).…”

Section: Use Of Deuterium Isotope Effects To Probe P450 Reactionsmentioning

confidence: 80%

The Use of Deuterium Isotope Effects to Probe the Active Site Properties, Mechanism of Cytochrome P450-Catalyzed Reactions, and Mechanisms of Metabolically Dependent Toxicity

Nelson¹,

Trager²

2003

Drug Metab Dispos

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142

121

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Critical elements from studies that have led to our current understanding of the factors that cause the observed primary deuterium isotope effect, (k H /k D )obs, of most enzymatically mediated reactions to be much smaller than the "true" or intrinsic primary deuterium isotope effect, k H /k D , for the reaction are presented. This new understanding has provided a unique and powerful tool for probing the catalytic and active site properties of enzymes, particularly the cytochromes P450 (P450). Examples are presented that illustrate how the technique has been used to determine k H /k D , and properties such as the catalytic nature of the reactive oxenoid intermediate, prochiral selectivity, the chemical and enzymatic mechanisms of cytochrome P450-catalyzed reactions, and the relative active site size of different P450 isoforms. Examples are also presented of how deuterium isotope effects have been used to probe mechanisms of the formation of reactive metabolites that can cause toxic effects.Historically, the determination of deuterium isotope effects has been a powerful tool to help unravel the intricacies of carbon-hydrogen bond cleavage and define the mechanism of specific chemical reactions. The intrinsic primary isotope effect, k H /k D , for a reaction is the magnitude of the isotope effect on the rate constant for the bond-breaking step (C-H versus C-D) of the reaction and is related to the symmetry of the transition state for that step. The larger the isotope effect, the more symmetrical the transition state, with the theoretical limit being 9 at 37°C in the absence of tunneling effects (Bell, 1974). The chemical events leading to the transition state and subsequent formation of products are the descriptors of a chemical mechanism. It is the relationship of k H /k D to transition state that provides mechanistic insight. Thus, k H /k D is the quantity that needs to be known, and for homogenous chemical reactions, the experimentally observed deuterium isotope effect, (k H /k D )obs, where (k H /k D )obs is defined as the ratio of a kinetic parameter such as V max or V max /K m obtained from a nondeuterated substrate to a deuterated substrate, is identical to k H /k D . This is generally not true of enzymatically mediated reactions and is the reason for the much less successful application of deuterium isotope effects to such reactions until the system was better understood. The experimentally observed isotope effect, (k H /k D )obs, was invariably found to be much smaller than k H /k D , the intrinsic isotope effect for that reaction, thereby obscuring both meaning and mechanism. Even more perplexing was the observation that (k H /k D

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Section: Use Of Deuterium Isotope Effects To Probe P450 Reactionsmentioning

confidence: 80%

The Use of Deuterium Isotope Effects to Probe the Active Site Properties, Mechanism of Cytochrome P450-Catalyzed Reactions, and Mechanisms of Metabolically Dependent Toxicity

Nelson¹,

Trager²

2003

Drug Metab Dispos

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142

121

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“…However, 2,3‐dihydroxypropyl mercapturic acid is not a specific biomarker of glycidyl ester exposure, as it was also confirmed to be a urinary metabolite of 3‐MCPD (as mentioned in the previous section). Furthermore, 2,3‐dihydroxypropyl mercapturic acid has been shown to be the urinary excretion product of several industrial chemicals (epichlorohydrin and several halogenated propanes or propanols, Gingell et al., ; James et al., ; Jones et al., ; Weber et al., ) which however do not normally occur environmentally. Eckert et al.…”

Section: Assessmentmentioning

confidence: 99%

“…However, 2,3-dihydroxypropyl mercapturic acid is not a specific biomarker of glycidyl ester exposure, as it was also confirmed to be a urinary metabolite of 3-MCPD (as mentioned in the previous section). Furthermore, 2,3-dihydroxypropyl mercapturic acid has been shown to be the urinary excretion product of several industrial chemicals (epichlorohydrin and several halogenated propanes or propanols, Gingell et al, 1985;James et al, 1981;Jones et al, 1974;Weber et al, 1995) which however do not normally occur environmentally. Eckert et al (2011) reported comparatively high background levels of 2,3-dihydroxypropylmercapturic acid in urine of smokers (median levels of 206 lg/g creatinine) and non-smokers (median levels of 217 lg/g creatinine) whose origin is still unknown.…”

Section: Glycidyl Estersmentioning

confidence: 99%

Risks for human health related to the presence of 3‐ and 2‐monochloropropanediol (MCPD), and their fatty acid esters, and glycidyl fatty acid esters in food

Wallace¹,

Alexander²,

Barregård³

et al. 2016

EFS2

129

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EFSA was asked to deliver a scientific opinion on free and esterified 3-and 2-monochloropropane-1, 2-diol (MCPD) and glycidyl esters in food. Esters of 3-and 2-MCPD and glycidol are contaminants of processed vegetable oils; free MCPDs are formed in some processed foods. The Panel on Contaminants in the Food Chain (CONTAM Panel) evaluated 7,175 occurrence data. Esters of 3-and 2-MCPD and glycidyl esters were found at the highest levels in palm oil/fat, but most vegetable oil/fats contain substantial quantities. Mean middle bound (MB) dietary exposure values to total 3-MCPD, 2-MCPD and glycidol, respectively, across surveys and age groups in µg/kg body weight (bw) per day were 0.2-1.5, 0.1-0.7 and 0.1-0.9; high exposure (P95) values were 0.3-2.6, 0.2-1.2 and 0.2-2.1. Animal studies show extensive hydrolysis of esterified 3-MCPD and glycidol following oral administration; esterified and free forms were assumed to contribute equally to internal exposures. Nephrotoxicity was consistently observed in rats treated with 3-MCPD. Data on 2-MCPD toxicity were insufficient for dose-response assessments. Chronic treatment with glycidol increased the incidence of tumours in several tissues of rats and mice, likely via a genotoxic mode of action. The Panel selected a BMDL 10 value for 3-MCPD of 0.077 mg/kg bw per day for induction of renal tubular hyperplasia in rats and derived a tolerable daily intake (TDI) of 0.8 µg/kg bw per day. The mean exposure to 3-MCPD was above the TDI for 'Infants', 'Toddlers' and 'Other children'. For glycidol, the Panel selected a T25 value of 10.2 mg/kg bw per day for neoplastic effects in rats. The margins of exposure (MoEs) were 11,300-102,000 and 4,900-51,000 across surveys and age groups at mean and P95 exposures, respectively. An exposure scenario for infants receiving formula only resulted in MoEs of 5,500 (mean) and 2,100 (P95). MoEs of 25,000 or higher were considered of low health concern. Amendment: A few editorial amendments were carried out that do not materially affect the contents of the outcome of this scientific output: on pages 5 and 91 'chorine' has been replaced with 'chlorine'; on page 52 the word 'it' has been replaced by 'its' in the first paragraph after Figure 7; on page 54 in the Repeated dose section the reference to MCPD has been replaced with 3-MCPD; on page 54 the 429.5 mg/kg bw day dose has been replaced with 29.5 mg/kg bw day; on page 55 in the first paragraph of the Hematology section the reference 'mg/kg per day' has been replaced with 'mg/kg bw per day; on page 55 the year for the reference Marchesini et al. has been changed from 1989 to 1986; on page 59, in the first paragraph of the Developmental toxicity section the word 'days' has been cancelled; on page 65 the reference 'Onami et al., 2014a,b' has been replaced with 'Onami et al., 2014b'; on page 85 first paragraph, reference to the lowest T25 of 10 has been replaced to 10.2. To avoid confusion, the older version has been removed from the EFSA Journal, but is available on request, as is a version sho...

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“…Nevertheless, in some cases, such as vicinal dihalogenated compounds, glutathione conjugation produces monosubstituted derivatives, which may cyclize into a highly electrophilic episulfonium ion (Figure 25.18) [47]. Nevertheless, in some cases, such as vicinal dihalogenated compounds, glutathione conjugation produces monosubstituted derivatives, which may cyclize into a highly electrophilic episulfonium ion (Figure 25.18) [47].…”

Section: Glutathione Conjugationmentioning

confidence: 99%

Biotransformations Leading to Toxic Metabolites

Macherey¹,

Dansette²

2015

The Practice of Medicinal Chemistry

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Identification of N-Acetylcysteine Conjugates of 1,2-Dibromo-3-chloropropane: Evidence for Cytochrome P450 and Glutathione Mediated Bioactivation Pathways

Cited by 19 publications

References 24 publications

The Use of Deuterium Isotope Effects to Probe the Active Site Properties, Mechanism of Cytochrome P450-Catalyzed Reactions, and Mechanisms of Metabolically Dependent Toxicity

The Use of Deuterium Isotope Effects to Probe the Active Site Properties, Mechanism of Cytochrome P450-Catalyzed Reactions, and Mechanisms of Metabolically Dependent Toxicity

Risks for human health related to the presence of 3‐ and 2‐monochloropropanediol (MCPD), and their fatty acid esters, and glycidyl fatty acid esters in food

Biotransformations Leading to Toxic Metabolites

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