Phosgene: A metabolite of chloroform

doi:10.1016/0006-291X(77)91166-4

Biochemical and Biophysical Research Communications

Volume 79, Issue 3, 7 December 1977, Pages 684-691

https://doi.org/10.1016/0006-291X(77)91166-4 Get rights and content

Abstract

Cysteine inhibited the $in vitro$ covalent binding of [¹⁴C] chloroform, (CHCl₃), to microsomal protein and concomitantly trapped a reactive metabolite, presumably phosgene (COCl₂), as 2-oxothiazolidine-4-carboxylic acid. When the incubation was conducted in an atmosphere of [¹⁸O] O₂, the trapped COCl₂ contained [¹⁸O]. These findings suggest that the CH bond of CHCl₃ is oxidized by a cytochrome P-450 monooxygenase to produce trichloromethanol, which spontaneously dehydrochlorinates to yield the toxic agent phosgene.

References (19)

C.D. Klaassen et al.
Toxicol. Appl. Pharmacol
(1966)
K.F. Ilett et al.
Exp. Mol. Pathol
(1973)
E.L. Docks et al.
Exp. Mol. Pathol
(1976)
I.G. Sipes et al.
Life Sci
(1977)
A.B. Eschenbrenner
J. Natl. Cancer Inst
(1944)
W.F. von Oettingen
The Halogenated Hydrocarbons of Industrial and Toxicological Importance
M.F. Conlon
Brit. Med. J
(1963)
B.R. Brown et al.
Anesthesiology
(1974)
H. Uehleke et al.
Arch. Toxicol
(1975)

There are more references available in the full text version of this article.

Cited by (174)

Diallyl disulfide, a garlic-rich compound ameliorates trichloromethane-induced renal oxidative stress, NFkB activation and apoptosis in rats
2019, Clinical Nutrition Experimental
Citation Excerpt :
The major reaction is hydrolysis by water, forming carbon dioxide and hydrochloric acid. Phosgene also undergoes attack by nucleophilic groups such as–NH2,OH, and SH in cellular macromolecules including the polar heads of phospholipids, proteins or enzymes, resulting in generation of covalent adducts [13–18]. These molecular adducts can interfere with molecular functions such as loss of enzyme activity, which may lead to loss of cellular activities and subsequently cell death [8,19].
The renal-protective effect of diallyl disulfide (DADS) on tricholoromethane (CHCl₃)-induced renal toxicity was investigated. Twenty five rats, divided into five groups of five animals each were used. CHCl₃ at the dose of 200 mg/kg was orally administered, and concomitantly treated with DADS (50 mg/kg), 5 days/week for a period of 3 weeks. Compared with control, there was no significant increase in kidney malondialdehyde (MDA), but a significant increase in levels of nuclear factor kappa B (NFkB) expressions, TUNEL positive cells (apoptosis), as well as hydrogen peroxide (H₂O₂), nitric oxide (NO) and reduced glutathione (GSH) concentrations. In addition, a significant decrease in expressions of kidney p53 and catalase (CAT) activity, and a non-significant decrease in glutathione peroxidase (GPx) activity were recorded following CHCl₃ administration. Conversely, following DADS treatment, there was a significant increase in the expressions of p53, and a significant and non-significant decrease in apoptotic positive cells and NFkB expressions respectively. Administration of DADS significantly reduced the levels of H₂O₂ and NO, but did not have effect on the level of GSH, while CAT and GPx activities were significant improved. Protection by DADS against TCM-induced renal-toxicity may therefore be via suppressions of NFkB activation, oxidative stress and apoptosis in rats.
Adsorption properties of the phosgene molecule on pristine graphyne, BN- and Si-doped graphynes: DFT study
2017, Results in Physics
Citation Excerpt :
Phosgene is released following the burning of carbon tetrachloride, trichloro-ethylene, and other halogenated hydrocarbons in common materials like plastic foam. This compound is very volatile and evaporates quickly at room temperature which this is said to cause rapid hydrolysis of phosgene in humid climates [1–7]. Graphyne is a type of carbon allotrope that contains sp and sp2 hybridized carbon network arranged in a crystal lattice.
This work explores the influence of adatoms such as boron (B), nitrogen (N), and silicon (Si) on the activity of graphyne toward phosgene adsorption by the density functional theory (DFT) calculations. The adsorbent systems include virgin and doped graphyne, in which each adatom (B, N, and Si) is substituted for the carbon atom in the aromatic core. The adsorption energy, energy gap, molecular electrostatic potential, density of state, and work function are estimated to predict the adsorption behavior of phosgene over graphyne. The obtained results demonstrate the progressive change in the phosgene adsorption and exhibit a notable increase in negative values for adsorption energy by doping heteroatom in the molecular structure of adsorbent. The electronic perturbations induced by doped atoms, especially Si, enhance the sensitivity of graphyne toward the adsorbed phosgene, and the electronic properties are changed after phosgene adsorption in all complexes. A sensible justification for this observation can be provided by the energy gap analysis. Over the range of our study, B, N and Si-doped clusters can be introduced as promising chemical sensors for phosgene monitoring.
Halogenated Hydrocarbons
2010, Comprehensive Toxicology, Second Edition
Halogenated hydrocarbons represent a large group of aromatic and aliphatic compounds with diverse industrial, agricultural, medical, and public health applications. Aliphatic halogenated hydrocarbons comprise many haloalkanes, haloalkenes, and haloalkynes which are released into the environment or detected in drinking water to which general public are exposed by various routes. These halogenated hydrocarbons can induce toxicity after biotransformation to multiple organs, especially kidney in experimental animals, and is a concern about the potential human health. The objective of this chapter is to review knowledge on the renal toxicology of representative haloalkanes and haloalkenes, the biochemical basis for their kidney selectivity, and, when possible, to correlate species- and sex-related differences in metabolism and nephrotoxicity.
Effects of concentrated drinking water injection on glutathione and glutathione-dependent enzymes in liver of Cyprinus carpio L.
2008, Chemosphere
Two drinking water production plants located in North Italy, collecting water from the River Po (Plants 1 and 2) were chosen for this study. Water samples were collected before and after the disinfection process and at two points along the piping system. Water samples were concentrated by the solid-phase extraction system and injected intraperitoneally into specimens of Cyprinus carpio. The concentration of water samples was 3 l/equiv. In order to assess the effects of the water samples on carp liver, total glutathione and glutathione-dependent enzymes, such as glutathione S-transferase, glutathione peroxidase, glutathione reductase and glyoxalase I, were measured following this treatment for 6 days at two experimental times (3 and 6 days). Both water plant-treated carp showed a general increase of the enzymatic activities of glutathione S-transferase, and glutathione reductase which might be employed as potential biomarkers of oxidative stress induced by disinfected river water. Plant 1-treated carp showed higher glyoxalase I and glutathione levels and lower glutathione peroxidase activity. A depleted level of total glutathione and of glyoxalase I for specimens of water plant 2 (for both experimental times), without correlation with the distances in the pipeline, suggests that river plant water can also lead to potentially adverse effects on selected biochemical parameters in C. carpio.
Mechanism of chloroform-induced renal toxicity: Non-involvement of hepatic cytochrome P450-dependent metabolism
2008, Toxicology and Applied Pharmacology
Chloroform causes hepatic and renal toxicity in a number of species. In vitro studies have indicated that chloroform can be metabolized by P450 enzymes in the kidney to nephrotoxic intermediate, although direct in vivo evidence for the role of renal P450 in the nephrotoxicity has not been reported. This study was to determine whether chloroform renal toxicity persists in a mouse model with a liver-specific deletion of the P450 reductase (Cpr) gene (liver-Cpr-null). Chloroform-induced renal toxicity and chloroform tissue levels were compared between the liver-Cpr-null and wild-type mice at 24 h following differing doses of chloroform. At a chloroform dose of 150 mg/kg, the levels of blood urea nitrogen (BUN) were five times higher in the exposed group than in the vehicle-treated one for the liver-Cpr-null mice, but they were only slightly higher in the exposed group than in the vehicle-treated group for the wild-type mice. Severe lesions were found in the kidney of the liver-Cpr-null mice, while only mild lesions were found in the wild-type mice. At a chloroform dose of 300 mg/kg, severe kidney lesions were observed in both strains, yet the BUN levels were still higher in the liver-Cpr-null than in the wild-type mice. Higher chloroform levels were found in the tissues of the liver-Cpr-null mice. These findings indicated that loss of hepatic P450-dependent chloroform metabolism does not protect against chloroform-induced renal toxicity, suggesting that renal P450 enzymes play an essential role in chloroform renal toxicity.
Hepatic antioxidant enzymes and total glutathione of Cyprinus carpio exposed to three disinfectants, chlorine dioxide, sodium hypochlorite and peracetic acid, for superficial water potabilization
2006, Chemosphere
This study was carried out in order to assess the effects of disinfectant-treatment on antioxidant response of Cyprinus carpio L. Therefore, enzymatic activities of glutathione S-transferases, glyoxalase I, glyoxalase II, glutathione peroxidases, glutathione reductase, catalase and total glutathione content of carp liver, exposed to surface water treated with three disinfectants for potabilization, sodium hypochlorite, chlorine dioxide and peracetic acid were investigated. Specimens of carp were exposed in four experimental tanks supplied with a continuous water flow from Lake Trasimeno (Italy), three of them treated with constant concentration of sodium hypochlorite, chlorine dioxide and peracetic acid, for 10 and 20 days, while the control tank was supplied with untreated lake water.
Differences in biochemical parameters were observed in specimens following exposure to these disinfectants and mainly, chlorine compounds induced marked biochemical variations of carp liver, compared to those induced by peracetic acid treatment. Our results showed that antioxidant parameters of Cyprinus carpio could be used as biomarkers of oxidative stress when this species is exposed to disinfectants for water potabilization.

View all citing articles on Scopus

View full text

Phosgene: A metabolite of chloroform

Abstract

Toxicol. Appl. Pharmacol

Exp. Mol. Pathol

Exp. Mol. Pathol

Life Sci

J. Natl. Cancer Inst

The Halogenated Hydrocarbons of Industrial and Toxicological Importance

Brit. Med. J

Anesthesiology

Arch. Toxicol