Chloroform
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Mechanism of action
The feasibility of an oxygen-independent mechanism of chloroform bioactivation was indicated by the covalent binding to lipid and protein occurring in anaerobic incubations of chloroform and microsomes in the presence of NADPH. Under these conditions, the loss of cytochrome p450 and the inhibition of related mono-oxygenases were also observed. The chloroform anoxic biotransformation was negligible in uninduced microsomes and seemed to be catalyzed mainly by phenobarbital-inducible p450 isozymes. Biotransformation could also be supported by NADH as the source of reducing equivalents. Anaerobic metabolism of chloroform led to decreased levels of the main phenobarbital-induced p450 isozymes even at low chloroform concentration, and did not affect benzo(a)pyrene hydroxylase activity. These effects were not decreased by thiolic compounds. The oxidation products of chloroform caused a general impairment of the monoxygenase system, probably related to the formation of protein aggregates with very high molecular weight. In the presence of physiological concentrations of GSH, the targets of aerobically-produced metabolite were lipids, and, to a smaller extent, p450. At low chloroform concentrations and/or in the presence of GSH, the most changes to microsomal structures seemed to be produced by the reductively-formed intermediates.
Pharmacokinetics
Half-life
Whole body: 1.5 hours; [TDR, p. 318]
After inhalation of approximately 5 mg (38)Cl-chloroform, about 80% of the chloroform was found to have been absorbed ... . Eight volunteers expired 18 to 67% of an oral dose of 500 mg (13)C-chloroform (in capsules of olive oil) unchanged; in two subjects, about half of the dose was eliminated in the expired air as (13)CO2. The decline in the concentration of chloroform in blood was described by a two-compartment model, with initial and second-phase half-lives of 14 and 90 min, respectively, averaged over four subjects.
In humans given a single oral dose of 0.5 g chloroform, about 50-52% of the dose was absorbed, and virtually all of the absorbed dose was metabolized to carbon dioxide. Blood levels peaked after 1.5 hr and declined in line with a two-compartment model with half-lives of 13 and 90 min, respectively ...
Absorption
Chloroform can be absorbed through lung, from GI tract and to some extent through skin. Inhalation route is ... primary source of ... absorption in man.
Chloroform is rapidly absorbed & distributed to all organs, with relatively high concn in nervous tissue. After intraduodenal injection of (14)C-chloroform to rats, 70% ... was found unchanged in expired air & 4% as (14)CO2(carbon dioxide) during 24 hr. ... Liver and, to much lesser extent, kidney were main organs in which CO2 was formed.
In man, pulmonary excretions of chloroform and its CO2 (carbon dioxide) metab account substantially for single oral dose of 0.5 or 1.0 g. Amongst 9 subjects, up to 68% of dose is excreted unchanged & up to 51% of CO2; not more than 4% of dose is excreted unchanged after 8 hr.
... /Chloroform crosses/ placenta rapidly and enters fetal circulation.
For more Absorption, Distribution and Excretion (Complete) data for Chloroform (50 total), please visit the HSDB record page.
Metabolism
When (14)C-chloroform was admin orally to mice, rats, & monkeys, radioactivity was found in expired air. Most of dose was excreted unchanged by monkeys, as (14)CO2 (carbon dioxide) by mice, & as both by rats. Three metabolites were detected in urine of rats & mice, one of which was identified as urea.
Haloforms are metabolized to carbon monoxide by hepatic microsomal mixed function oxidases & this reaction is markedly stimulated by sulfhydryl cmpd. Max stimulation occurred at 0.5 mmol glutathione. A mechanism for conversion to carbon monoxide is proposed.
Trihalomethanes (haloforms) were metab to carbon monoxide by rat liver microsomal fraction requiring nadph & molecular oxygen. Metabolism followed halide order; thus, chloroform yielded smallest amt. Results suggest cytochrome p450 dependent system.
Deuterium-labeled chloroform was less toxic and less readily metabolized than /normal/ chloroform, suggesting that the cleavage of the C-H bond is the rate-limiting step in the process resulting in hepatotoxicity.
For more Metabolism/Metabolites (Complete) data for Chloroform (22 total), please visit the HSDB record page.
Chloroform in absorbed mainly through the lungs. Once in the body it concentrates in lipid-containing organs such as the adipose tissue, the central nervous system, kidney and liver. It is eliminated unchanged in expired air or metabolized by the liver via a cytochrome P450 mechanism and excreted in the urine and faeces. (A11)
External links
Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.