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  • 1.
    Davies, Ronnie
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Rydberg, Per
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Westberg, Emelie
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Motwani, Hitesh V.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Johnstone, Erik
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    A New General Pathway for Synthesis of Reference Compounds of N-Terminal Valine-Isocyanate Adducts2010In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 23, no 3, 540-546 p.Article in journal (Refereed)
    Abstract [en]

    Adducts to Hb could be used as biomarkers to monitor exposure to isocyanates. Particularly useful is the measurement of carbamoylation of N-terminal valines in Hb, after detachment as hydantoins. The synthesis of references from the reactive isocyanates, especially diisocyanates, has been problematic due to side reactions and polymerization of the isocyanate starting material. A simpler, safer, and more general method for the synthesis of valine adducts of isocyanates has been developed using N-[(4-nitrophenyl)-carbamate]valine methylamide (NPCVMA) as the key precursor to adducts of various mono- and diisocyanates of interest. By reacting NPCVMA with a range of isocyanate-related amines, carbamoylated valines are formed without the use of the reactive isocyanates. The carbamoylated products synthesized here were cyclized with good yields of the formed hydantoins. The carbamoylated derivative from phenyl isocyanate also showed quantitative yield in a test with cyclization tinder the conditions used in blood. This new pathway for the preparation of N-carbamoylated model compounds overcomes the above-mentioned problems in the synthesis and is a general and simplified approach, which could make such reference compounds of adducts to N-terminal valine from isocyanates accessible for biomonitoring purposes. The synthesized hydantoins corresponding to adducts from isocyanic acid, methyl isocyanate, phenyl isocyanate, and 2,6-toluene diisocyanate were characterized by LC-MS analysis. The background level of the hydantoin from isocyanic acid in human blood was analyzed with the LC-MS conditions developed.

  • 2.
    Motwani, Hitesh
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Fred, Charlotta
    Haglund, Johanna
    Golding, Bernard
    Törnqvist, Margareta
    Cob(I)alamin as an analytical tool to study 1,3-butadiene metabolism in human, mouse and rat S9 liver fractions2007In: Gordon Research Conference on Vitamin B12 and Corphins, 2007Conference paper (Other (popular science, discussion, etc.))
  • 3.
    Motwani, Hitesh
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Shimakoshi, Hisashi
    Department of Chemistry and Biochemistry, Kyushu University.
    Golding, Bernard
    School of Chemistry, Newcastle University.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Hisaeda, Yoshio
    Department of Chemistry and Biochemistry, Kyushu University.
    Formation of an alkylcobyrinate from sucralose and mechanistic aspects of its Co-C bond cleavagesIn: European Journal of Inorganic Chemistry, ISSN 1434-1948, E-ISSN 1099-1948Article in journal (Other academic)
  • 4.
    Motwani, Hitesh
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Shimakoshi, Hisashi
    Hisaeda, Yoshio
    Golding, Bernard
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Reductive dechlorination of sucralose mediated by vitamin B12 derivatives2008Conference paper (Other academic)
  • 5.
    Motwani, Hitesh
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Cob(I)alamin for measuring interspecies variation in butadiene epoxide metabolism in S9 liver fractions and evaluation of in vivo doses estimated from enzyme kinetics and from hemoglobin adductsIn: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333Article in journal (Other academic)
  • 6.
    Motwani, Hitesh
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Quantitative analysis by liquid chromatography-tandem mass spectrometry of glycidamide using cob(I)alamin trapping method: Validation and application to in vitro metabolism of acrylamideIn: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778Article in journal (Other academic)
  • 7.
    Motwani, Hitesh V
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Fred, Charlotta
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Haglund, Johanna
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Golding, Bernard T
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Cob(I)alamin for trapping butadiene epoxides in metabolism with rat S9 and for determining associated kinetic parameters2009In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 22, no 9, 1509-1516 p.Article in journal (Refereed)
    Abstract [en]

    The reduced state of vitamin B(12), cob(I)alamin, acts as a supernucleophile that reacts ca. 10(5) times faster than standard nucleophiles, for example, thiols. Methods have been developed for trapping electrophilically reactive compounds by exploiting this property of cob(I)alamin. 1,3-Butadiene (BD) has recently been classified as a group 1 human carcinogen by the International Agency for Research on Cancer (IARC). The carcinogenicity of BD is considered to be dependent on the activation or deactivation of the reactive metabolites of BD, that is, the epoxides (oxiranes) 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane (DEB), and 1,2-epoxy-3,4-butanediol (EBdiol). Cytochrome P450 (P450) isozymes are involved in oxidation of BD to EB and further activation to DEB. EB and DEB are hydrolyzed by epoxide hydrolases (EH) to 3,4-dihydroxy-1-butene (BDdiol) and EBdiol, respectively. EBdiol can also be formed by oxidation of BDdiol. In the present study, cob(I)alamin was used for instant trapping of the BD epoxide metabolites generated in in vitro metabolism to study enzyme kinetics. The substrates EB, DEB, and BDdiol were incubated with rat S9 liver fraction, and apparent K(m) and apparent V(max), were determined. The ratio of conversion of EB to DEB (by P450) to the rate of deactivation of DEB by EH was 1.09. Formation of EBdiol from hydrolysis of DEB was ca. 10 times faster than that from oxidation of BDdiol. It was also found that the oxidation of EB to DEB was much faster than that of BDdiol to EBdiol. The study offers comparative enzyme kinetic data of different BD metabolic steps, which is useful for quantitative interspecies comparison. Furthermore, a new application of cob(I)alamin was demonstrated for the measurement of enzyme kinetics of compounds that form electophilically reactive metabolites.

  • 8.
    Motwani, Hitesh V.
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Qiu, Shiran
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Golding, Bernard T.
    Kylin, Henrik
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Cob(I)alamin reacts with sucralose to afford an alkylcobalamin: Relevance to in vivo cobalamin and sucralose interaction2011In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 49, no 4, 750-757 p.Article in journal (Refereed)
    Abstract [en]

    Vitamin B(12), viz., cyano- or hydroxo-cobalamin, can be chemically or enzymatically converted into the derivatives methyl- and adenosyl-cobalamin, which are complex organometallic cofactors associated with several cobalamin-dependent enzymes. The reduced form of vitamin B(12), cob(I)alamin {Cbl(I)}, obtained by reduction of hydroxocobalamin (OH-Cbl) with e.g. sodium borohydride, is one of the most powerful nucleophiles known. Cbl(I) was shown to react readily with the synthetic sweetener sucralose (1,6-dichloro-1,6-dideoxy-β-d-fructofuranosyl-4-chloro-4-deoxy-α-d-galactopyranoside) in an aqueous system to form an alkylcobalamin (Suc-Cbl). This occurred by replacement of one of the three chlorine atoms of sucralose with a cobalamin moiety. The efficiency of trapping sucralose in presence of excess Cbl(I) was estimated to be >90%. Furthermore, in an in vitro study using human liver S9 with NADPH regeneration, in presence of OH-Cbl and sucralose, Suc-Cbl was shown to be formed. The Suc-Cbl was characterized primarily by LC-ESI(+)-MS/MS. Given the human consumption of sucralose from food and beverages, such a reaction between the sweetener and reduced vitamin B(12) could occur in vivo.

  • 9.
    Motwani, Hitesh Vijay
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Cob(I)alamin as a Quantitative Tool for Analysis, Metabolism and Toxicological Studies of Electrophilic Compounds: Butadiene Epoxides, Glycidamide and Sucralose2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Vitamin B12 can be reduced to cob(I)alamin [Cbl(I)], which is one of the most powerful nucleophiles known and referred to as a “supernucleophile”. Cbl(I) was applied as a tool in toxicological studies of the air pollutant 1,3-butadiene (BD), the toxicant acrylamide (AA) present in many foods, and the artificial sweetener sucralose.

    BD, a human carcinogen, is metabolised to genotoxic epoxides, two monoepoxides and the most potent diepoxybutane (DEB). AA, classified as a probable human carcinogen, is metabolised to the genotoxic epoxide glycidamide (GA). Due to their reactivity, quantitative analysis of the epoxides presents an analytical challenge. By using Cbl(I) for trapping, a sensitive and accurate method to quantify the epoxides as alkylcobalamins by LC-MS/MS in metabolism studies was developed and validated.

    Using the Cbl(I) method, enzyme kinetic parameters, Vmax and Km, were determined for the metabolic steps associated with the BD epoxides and with the formation of GA from AA, in liver S9 fractions of human, mouse and rat.

    An approach to estimate dose in vivo (i.e. area under concentration time curve, AUC) of BD epoxides by scaling the enzyme kinetic data was designed. The AUCs obtained from in vitro were evaluated by comparing with AUCs in vivo that were calculated from published haemoglobin adduct data. The AUCs from in vitro and in vivo showed to be in agreement with each other for mouse and rat, and this evaluation allowed prediction of the unknown AUC of DEB in human from BD exposure. This approach has a potential to reduce animal experiments in the future.

    Sucralose is of concern due to its chlorinated structure and persistence in the aquatic environment. It was demonstrated that Cbl(I) reacts with sucralose, also under in vitro physiological conditions, which might have toxicological significance. The demonstrated reaction also suggested a potential role for Cbl(I) in dehalogenation/degradation of sucralose. This was evaluated and shown possible using heptamethyl cobyrinate, a model compound for cobalamin.

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