104713-70-4Relevant academic research and scientific papers
Fourier-Transform Ion Cyclotron Resonance Mass Spectrometric Evidence for the Formation of α-Chloroenethiolates and Thioketenes from Chloroalkene-Derived, Cytotoxic 4-Thiaalkanoates
Zhang, Tian-lan,Wang, Liping,Hashmi, Mazzaz,Anders, M. W.,Thorpe, Colin,Ridge, Douglas P.
, p. 907 - 910 (1995)
The cytotoxicity of chloroalkene-derived cysteine S-conjugates is thought to be associated with the formation of α-chloroenethiolates and thioketenes as reactive intermediates. Recent studies indicate that the formation of 1,2-dichloroethenethiolate, which may give rise to chlorothioketene, is a key step in the bioactivation of 5,6-dichloro-4-thia-5-hexenoic acid (Fitzsimmons et al. (1995) Biochemistry 34, 4276-4286). We report here the use of Fourier-transform ion cyclotron resonance mass spectrometry to provide the first direct evidence for the formation of α-chloroenethiolate and thioketene species from a cytotoxic 4-thiaalkanoate. The bioactivation of 5,6-dichloro-4-thia-5-hexenoic acid involves conversion to the corresponding CoA thioester 5,6-dichloro-5-hexenoyl-CoA and subsequent processing by the fatty acid β-oxidation pathway. It has been proposed that the bioactivation of 5,6-dichloro-4-thia-5-hexenoyl-CoA involves loss of 1,2-dichloroethenethiolate, followed by loss of chloride to form chlorothioketene. 1,2-Dichloroethenethiolate and related α-chloroalkenethiolates have not been observed directly in aqueous solution. Fourier-transform ion cyclotron resonance mass spectrometric experiments show that S-propyl 5,6-dichloro-4-thia-5-hexenethioate reacts in the gas phase with base (hydroxide ion) to release 1,2-dichloroethenethiolate, which is observed directly in the mass spectrum of the products of the gas-phase reaction. Furthermore, the elimination of chloride from 1,2-dichloroethenethiolate on collision-induced decomposition is facile and provides evidence for chlorothioketene formation. Preliminary evidence for the formation of 1,2-dichloroethenethiolate and chlorothioketene from S-(1,2-dichlorovinyl)-N-acetyl-L-cysteine methyl ester was also obtained. These observations support the intermediacy of α-chloroenethiolates and chlorothioketenes in the bioactivation of cytotoxic, chloroalkene-derived 4-thiaalkanoates and cysteine S-conjugates and demonstrate the utility of Fourier-transform ion cyclotron mass spectrometry in studying the formation of reactive intemediates.
Sulfoxidation of mercapturic acids derived from tri- and tetrachloroethene by cytochromes P450 3A: A bioactivation reaction in addition to deacetylation and cysteine conjugate β-lyase mediated cleavage
Werner, Michael,Birner, Gerhard,Dekant, Wolfgang
, p. 41 - 49 (2007/10/03)
In the present study we investigated the formation of sulfoxides from N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine (N-Ac-TCVC), N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine (N-Ac-1,2-DCVC), and N-acetyl-S-(2,2-dichlorovinyl)-L-cysteine (N-Ac-2,2-DCVC), which are formed in the glutathione dependent bioactivation of tri- and tetrachloroethene. The first aim was to elucidate the enzymes involved in these oxidation reactions. N-Ac-TCVC, N-Ac-1,2-DCVC, and N-Ac-2,2-DCVC are oxidized to the corresponding sulfoxides mainly, if not exclusively, by cytochrome P450 enzymes in liver microsomes of untreated male rats, since no role for the flavin-containing monooxygenase (FMO) could be demonstrated by heat inactivation experiments and by the use of n-octylamine. The sulfoxidation rates were increased when using liver microsomes of phenobarbital and dexamethasone pretreated male rats as well as liver microsomes of dexamethasone pretreated female rats, while no sulfoxide formation was observed in liver microsomes of untreated female rats, suggesting an involvement of cytochrome P450 3A. Also, troleandomycin, a specific chemical inhibitor for cytochrome P450 3A, drastically reduced sulfoxidation rates. The observed rates of sulfoxidation also correlated well with the rates of oxidation of testosterone at the 6-β-position, a specific marker for P450 3A activity. The second aim of this study was to compare the cytotoxicity of the sulfoxides with the cytotoxicity of the corresponding mercapturic acids in isolated rat renal epithelial cells. Both mercapturic acids and the corresponding sulfoxides were cytotoxic. Cytotoxicity of the mercapturic acids could be blocked by (aminooxy)acetic acid (AOAA), an inhibitor of cysteine conjugate β-lyase, while the cytotoxicity of the sulfoxides was not influenced by this treatment. Moreover, the sulfoxides were significantly more cytotoxic than the corresponding mercapturic acids at equimolar doses. The results show that mercapturic acids derived from TRI and PER are oxidized to sulfoxides by microsomal monooxygenases from rat liver. The cytotoxicity of the produced sulfoxides could not be reduced by AOAA, consistent with a role of the sulfoxides as direct acting electrophiles (i.e., Michael acceptor substrates).
