Disease relevance of trichloromethane

• Our results suggest that the initial toxicity of CCl4 for the Ca2+ pump results from the metabolism of CCl4 to the CCl3. radical [1].
• Adduct formation between CCl3* and DNA is thought to function as initiator of hepatic cancer [2].
• Reductive dehalogenation of the trichloromethyl group of nitrapyrin by the ammonia-oxidizing bacterium Nitrosomonas europaea [3].
• Hypoxia or pretreatment with phenobarbital has been reported to enhance the hepatotoxicity of CCl4 in vivo; these treatments also produced an increase in the biliary concentration of the PBN/.CCl3 radical adduct and in the .CCl3-derived PBN/.CO(-)2 radical adduct as well [4].
• The data in this report suggest that localized hepatic edema which occurs soon after administration of CCl4 involves activation of Kupffer cells, and that trichloromethyl radical production may be a separate but related process occurring in parenchymal cells [5].

High impact information on trichloromethane

• They suggest that hyperbaric O2 might decrease free radical formation in the liver in vivo and promote formation of CCl(3)00. from CCl3.. This should result in diminished CCl4-induced lipid peroxidation and liver damage [6].
• Microsomal reductive metabolism of PEN led to formation of a metabolite tentatively identified as a molecule formed by dimerization of the radical species produced by cleavage of chlorine from the trichloromethyl moiety of penclomedine [7].
• It was previously shown that the reductive debromination of BrCCl3 to trichloromethyl radical by human hemoglobin leads to formation of dissociable altered heme products, two of which are identical to those formed from myoglobin and one which is novel [8].
• In an earlier study employing electron spin resonance and spin-trapping techniques, we demonstrated that trichloromethyl (13.CCl3) radicals are readily observed in rat liver microsomes metabolizing 13CCl4, and that the same radical could be shown to form in vivo in the liver of intact rats given a single dose of 13CCl4 [9].
• CCl4 is activated by cytochrome (CYP)2E1, CYP2B1 or CYP2B2, and possibly CYP3A, to form the trichloromethyl radical, CCl3*. This radical can bind to cellular molecules (nucleic acid, protein, lipid), impairing crucial cellular processes such as lipid metabolism, with the potential outcome of fatty degeneration (steatosis) [2].

Biological context of trichloromethane

• The data obtained showed that the inhibition is sensitive to stereochemical effects and that the trichloromethyl terminus of the molecule is recognized by the binding site [10].
• Trichloromethyl and trichloromethyl peroxyl radicals are known to be produced during CCl4 biotransformation and are considered to be critical for deleterious effects of this haloalkane [11].
• On the 20th day of gestation, the foetal liver shows cytochrome P-450 dependent metabolic activity and constitutes a good model illustrating the hypothesis of calcium pump inhibition by .CCl3 radicals without lipoperoxidation [12].
• Kinetics of the reactions of chlorinated methyl radicals (CH2Cl, CHCl2, and CCl3) with NO2 in the temperature range 220-360 K [13].
• The pathway includes one-electron reduction of CCl4 by the Cu(II):PDTC complex, condensation of trichloromethyl and thiyl radicals, and hydrolysis of a labile thioester intermediate [14].

Anatomical context of trichloromethane

• Isolated rat liver mitochondria incubated under hypoxic conditions with succinate and ADP were found able to activate CCl4 to a free-radical species identified as trichloromethyl free radical (CCl3) by e.s.r. spectroscopy coupled with the spin-trapping technique [15].
• These hepatotoxic effects of CCl4 are dependent upon its metabolic activation in the liver endoplasmic reticulum to reactive intermediates, including the trichloromethyl free radical [16].
• This polypeptide, which was shown to disappear from liver microsomes following treatment of rats with CCl4 was demonstrated in the accompanying report to be the form of cytochrome P-450 specifically required for production of the highly reactive trichloromethyl radical in a reconstituted monooxygenase system [17].
• These results suggest that Cr(III) preadministered to mice might act as a radical scavenger to CCl4 to form trichloromethyl radicals which are a major initial product of CCl4 in liver cells [18].
• The results confirm that covalent binding of the CCl3* radical to cell components initiates the inhibition of lipoprotein secretion and thus steatosis, whereas reaction with oxygen, to form CCl3-OO*, initiates lipid peroxidation [19].

Associations of trichloromethane with other chemical compounds

• A series of derivatives of N-methylformamide (NMF), an experimental antitumor agent, has been prepared, having the general formula R3C(X)NR1R2 where R1 = H, CH3, CD3, CH2CF3, CH2CH2Cl, cyclopropyl, C2H5, CH2OH, CH2OR, CH2N(CH3)2; R2 = H, CH3; R3 = H, CF3, CCl3, CH3, Ph, NHCH3, N(CH3)2; and X = O, S, NH [20].
• Data are also presented which show that this form of cytochrome P-450 was capable of generating the trichloromethyl radical from CCl4 in a reconstituted system containing the purified cytochrome, NADPH-cytochrome P-450 reductase, NADPH, CCl4, and the spin-trapping agent, phenyl-t-butyl nitrone [21].
• Confirmation of assignment of the trichloromethyl radical spin adduct detected by spin trapping during 13C-carbon tetrachloride metabolism in vitro and in vivo [22].
• Carbon tetrachloride (CCl4) is metabolized by cytochrome P450 to form a reactive trichloromethyl radical that triggers a chain of lipid peroxidation [23].
• 3. In isolated microsomes, ethanol feeding in HF or LF diets increased CCl3 formation by approx. 8-fold and 4-fold, respectively, over control values [24].

Gene context of trichloromethane

• The stoichiometric reductive debromination of BrCCl3 to a trichloromethyl radical by myoglobin caused the prosthetic heme to become covalently cross-linked to the protein moiety and transformed myoglobin from an oxygen storage protein to an oxidase [25].
• Evidence to support this hypothesis was developed by adding bovine serum albumin (BSA) to an aqueous solution of the trichloromethyl radical adduct of PBN [26].
• Furthermore, the frequency of appearances of ESR signals of .CCl3 in the liver homogenate of mice 1 min after CCl4 administration was markedly decreased by Cr(III) preadministration, similarly to DL-alpha-tocopherol [27].
• Certain reaction characteristics of the trichloromethyl fulfenyl fungicides with GPDH were found to be similar to those of chlorothalonil [28].
• Mechanistic studies demonstrated that bicyclol significantly inhibited CCl(4)-induced lipid peroxidation of liver microsomes and (14)CCl(4) covalent binding to microsomal lipids and proteins in vitro, and decreased the level of the trichloromethyl free radical (*CCl(3)) generated from CCl(4) metabolism by NADPH-reduced liver microsomes [29].

Analytical, diagnostic and therapeutic context of trichloromethane

• 4. Although pulse radiolysis and other evidence support the very rapid formation of the trichloromethyl peroxy radical from the trichloromethyl radical and oxygen, no clear evidence for the trapping of the peroxy radical was obtainable [30].
• The resulting covalently modified lipids contain two different types of fatty acids: a group of monomeric trichloromethyl fatty acid residues, usually with one double bond less than the precursor fatty acids, and a group of fatty acids that are not sufficiently volatile for gas chromatography [31].
• The activity of NADPH-cytochrome C reductase, which presumably catalyzes the formation of .CCl3 from CCl4 in liver microsomes, was depressed by Cr(III) administration and kept at a level lower than that of the control group for at least 2 hr after CCl4 dosing [27].

References