Metabolism of dihalomethanes to carbon monoxide—III

Kubic, Virginia; Anders, M.W.

doi:10.1016/0006-2952(78)90143-0

Cited by 89 publications

(25 citation statements)

References 24 publications

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“…Rat heart H9c2 cells were treated with the CO-generating molecule dichloromethane (DCM) to increase cellular CO levels via cytochrome P 450 activity (Kubic and Anders, 1975). CO dose and CO time responses are shown in Fig.…”

Section: Role Of H 2 Omentioning

confidence: 99%

A new activating role for CO in cardiac mitochondrial biogenesis

Suliman

Carraway

Tatro

et al. 2007

Journal of Cell Science

192

182

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To investigate a possible new physiological role of carbon monoxide (CO), an endogenous gas involved in cell signaling and cytotoxicity, we tested the hypothesis that the mitochondrial generation of reactive oxygen species by CO activates mitochondrial biogenesis in the heart. In mice, transient elevations of cellular CO by five- to 20-fold increased the copy number of cardiac mitochondrial DNA, the content of respiratory complex I-V and interfibrillar mitochondrial density within 24 hours. Mitochondrial biogenesis is activated by gene and protein expression of the nuclear respiratory factor 1 (NRF1) and NRF2, of peroxisome proliferator-activated receptor gamma co-activator-1α, and of mitochondrial transcription factor A (TFAM), which augmented the copy number of mitochondrial DNA (mtDNA). This is independent of nitric oxide synthase (NOS), as demonstrated by the identical responses in wild-type and endothelial NOS (eNOS)-deficient mice, and by the inhibition of inducible NOS (iNOS). In the heart and in isolated cardiomyocytes, CO activation involved both guanylate cyclase and the pro-survival kinase Akt/PKB. Akt activation was facilitated by mitochondrial binding of CO and by production of hydrogen peroxide (H2O2). Interference with Akt activity by blocking PI 3-kinase and by mitochondrial targeting of catalase to scavenge H2O2 prevented binding of NRF1 to the Tfam promoter, thereby connecting mitochondrial H2O2 to the pathway leading to mtDNA replication. The findings disclose mitochondrial CO and H2O2 as new activating factors in cardiac mitochondrial biogenesis.

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Section: Role Of H 2 Omentioning

confidence: 99%

A new activating role for CO in cardiac mitochondrial biogenesis

Suliman

Carraway

Tatro

et al. 2007

Journal of Cell Science

192

182

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“…§1734 solely to indicate this fact. (5) and GSH conjugation (6). The oxidation is catalyzed primarily by cytochrome P450 2E1 (7,8), and the conjugation is catalyzed primarily by GSH S-transferase 5-5 and related theta-class enzymes (9).…”

mentioning

confidence: 99%

“…Our efforts to demonstrate the GSH-dependent conjugation through depletion of GSH within the cells were not particularly successful, and we also considered the possibility that the putative S-(l-halomethyl)GSH products might be unable to cross cell membranes. Therefore, we introduced a plasmid expression vector containing a cDNA clone for rat GSH S-transferase 5 pared by adding bromomethyl acetate (Aldrich, 250 mg, 1.63 mmol) dropwise to a 7-ml solution of GSH (272 mg, 0.89 mmol) and Nae (67 mg, 2.9 mmol, 3 equivalents) in dry CH30H; the product precipitated immediately and was recovered by centrifugation (3 x 103 x g, 10 min), dried under N2, and stored in a dessicator at -20°C. Attempts to record NMR and mass spectra were unsuccessful, primarily due to lack of solubility in nonaqueous solvents; however, analysis (20) (10-20%6 yield) eluted =1 min after the starting material (dGuo or dCyd) and was collected and recovered by lyophilization, rechromatography, and repeated lyophilization to remove salt.…”

mentioning

confidence: 99%

Expression of mammalian glutathione S-transferase 5-5 in Salmonella typhimurium TA1535 leads to base-pair mutations upon exposure to dihalomethanes.

Thier

Taylor

Pemble

et al. 1993

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

179

165

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Dihalomethanes can produce liver tumors in mice but not in rats, and concern exists about the risk of these compounds to humans. Glutathione (GSH) conjugation of dihalomethanes has been considered to be a crifical event in the bioactivation process, and risk assessment is based upon this premise; however, there is little experimental support for this view or information about the basis of genotoxicity. A plasmid vector containing rat GSH S-transferase 5-5 was transfected into the SalmoneUla typhimurium tester strain TA1535, which then produced active enzyme. The transfected bacteria produced base-pair revertants in the presence ofethylene dihalides or dihalomethanes, in the order CH2Br2 > CH2BrCl > CH2CI2. However, revertants were not seen when cells were exposed to GSH, CH2Br2, and an amount of purified GSH S-ransferase 5-5 (20-fold excess in amount of that expressed within the cells). HCHO, which is an end product of the reaction of GSH with dihalomethanes, also did not produce mutations. S-(1-Acetoxymethyl)GSH was prepared as an analog of the putative S-(1-halomethyl)GSH reactive intermediates. This analog did not produce revertants, consistent with the view that activation of dihalomethanes must occur within the bacteria to cause genetic damage, presenting a model to be considered in studies with mammalian cells. S-(1-Acetoxymethyl)GSH reacted with 2'-deoxyguanosine to yield a major adduct, identified as S-[l-(N2-deoxyguanosinyl)methyl]GSH.

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“…Reductive dehalogenation accounts for the conversion of carbon tetrachloride to chloroform (1) and chloroform to methylene chloride (2) as well as for the conversion of DDT to DDD (3). A transferase system has been described to account for the replacement of a halogen by glutathione with concomitant dehalogenation and subsequent mercapturic acid formation (4,5), Kubic et al (6) have described the conversion of dichloromethane to carbon monoxide by microsomes which would indicate a partial oxidation reaction. Recently Ahmed et al (7) reported a cytosol glutathione transferase which converted dihalomethanes to formaldehyde and inorganic halides.…”

mentioning

confidence: 99%

“…MeOCF2CC12-+ MeOH = MeOCF2CHCl2 + MeO- (6) pound then undergoes a nucleophilic attack and binds with the methanol ion. Therefore this reaction is very much like that which is proposed for the enzymatic reduction of halothane.…”

mentioning

confidence: 99%

Dechloriation mechanisms of chlorinated olefins.

Dyke¹

1977

Environ Health Perspect

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The dechlorination of chlorinated hydrocarbons has been examined in detail. The reaction is catalyzed by cytochrome P450 and occurs optimally in the presence of oxygen although some dechlorination may occur under anaerobic conditions. Halothane has been shown to undergo an oxidative dechlorination and a reductive defluorination. Enzymatic attack of chlorinated olefins and hydrocarbons is not on the carbon-halogen bond. Oxidative dechlorination of hydrocarbons is apparently initiated by an attack on the carbon atom and the halogen is then released from the oxidized carbon. The chlorinated olefins, on the other hand, are not easily dechlorinated enzymatically. The chlorines migrate readily across the double bond, therefore, cyclic chloronium ions must occur as intermediates. It is not clear at this time if epoxides are also intermediates in this conversion.Halogenated compounds when put in a biologic system are converted to a variety of products, which indicates that there is either more than one mechanism controlling the dehalogenation or there is more than one step in the dehalogenation reaction. The actual situation may represent a combination of these possibilities. There have been a number of mechanisms suggested to account for the reaction of the halogenated compounds known to occur. Reductive dehalogenation accounts for the conversion of carbon tetrachloride to chloroform (1) and chloroform to methylene chloride (2) as well as for the conversion of DDT to DDD (3). A transferase system has been described to account for the replacement of a halogen by glutathione with concomitant dehalogenation and subsequent mercapturic acid formation (4,5) well as the metabolic or physiologic conditions and therefore no single mechanism will apply for all classes of compounds.Studies of enzymatic dehalogenation have largely centered on the saturated hydrocarbons and for that reason this report will begin with a discussion of the metabolism of a series of chlorinated ethanes and propanes. It should be emphasized that throughout this discussion there is a considerable amount of speculative thought although as much as possible the speculation will be separated from the actual facts.A basic rule can be applied to enzymatic dehalogenation irregardless of whether it is oxidative or reductive, that is, there is no direct attack on the carbon-halogen bond, but the attack is on the carbon causing, secondarily the halogen release. Also, it should be remembered that when dealing with mechanisms of this type one should not necessarily think that what applies to one halogenated compound applies to all of similar structure.Our initial studies on this subject began with a series of chlorinated ethanes and propanes to determine the relative rates of dechlorination and the effects of various amounts of halogenation on these rates. Table 1

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Metabolism of dihalomethanes to carbon monoxide—III

Cited by 89 publications

References 24 publications

A new activating role for CO in cardiac mitochondrial biogenesis

A new activating role for CO in cardiac mitochondrial biogenesis

Expression of mammalian glutathione S-transferase 5-5 in Salmonella typhimurium TA1535 leads to base-pair mutations upon exposure to dihalomethanes.

Dechloriation mechanisms of chlorinated olefins.

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