Dichloromethane Potentiation of Carbon Tetrachloride Hepatotoxicity in Rats

Kim, Young C.

doi:10.1006/faat.1996.2266

Cited by 9 publications

(4 citation statements)

References 2 publications

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“…Previous studies showed little evidence of oxidative stress produced by the individual compounds when administered in vivo at doses even higher than the ones used in the present study [9, 24, 27, 28, 52] (Table 1) and we did not find changes in GSH levels with any of the individual compounds administered at the high dose for three days in the pilot study either (Table 1). …”

Section: Discussioncontrasting

confidence: 57%

Micronuclei in Bone Marrow and Liver in relation to Hepatic Metabolism and Antioxidant Response due to Coexposure to Chloroform, Dichloromethane, and Toluene in the Rat Model

Belmont-Díaz

López-Gordillo

Garduño

et al. 2014

BioMed Research International

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Genotoxicity in cells may occur in different ways, direct interaction, production of electrophilic metabolites, and secondary genotoxicity via oxidative stress. Chloroform, dichloromethane, and toluene are primarily metabolized in liver by CYP2E1, producing reactive electrophilic metabolites, and may also produce oxidative stress via the uncoupled CYP2E1 catalytic cycle. Additionally, GSTT1 also participates in dichloromethane activation. Despite the oxidative metabolism of these compounds and the production of oxidative adducts, their genotoxicity in the bone marrow micronucleus test is unclear. The objective of this work was to analyze whether the oxidative metabolism induced by the coexposure to these compounds would account for increased micronucleus frequency. We used an approach including the analysis of phase I, phase II, and antioxidant enzymes, oxidative stress biomarkers, and micronuclei in bone marrow (MNPCE) and hepatocytes (MNHEP). Rats were administered different doses of an artificial mixture of CLF/DCM/TOL, under two regimes. After one administration MNPCE frequency increased in correlation with induced GSTT1 activity and no oxidative stress occurred. Conversely, after three-day treatments oxidative stress was observed, without genotoxicity. The effects observed indicate that MNPCE by the coexposure to these VOCs could be increased via inducing the activity of metabolism enzymes.

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Section: Discussioncontrasting

confidence: 57%

Micronuclei in Bone Marrow and Liver in relation to Hepatic Metabolism and Antioxidant Response due to Coexposure to Chloroform, Dichloromethane, and Toluene in the Rat Model

Belmont-Díaz

López-Gordillo

Garduño

et al. 2014

BioMed Research International

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“…When necessary, dichloromethane was also given intraperitoneally at a dose of 6 mmol/kg simultaneously with an injection of CdCl 2 , and the same dose of the reagent was administered again 6 hours later. Dichloromethane is converted to CO in vivo through the reaction of P450 cytochromes (8,9). We examined temporal changes in percentages of carboxyhemoglobin (HbCO) contents in venous blood samples collected from rats undergoing the current protocols for the dichloromethane administration according to the previous method (8).…”

Section: Methodsmentioning

confidence: 99%

“…Dichloromethane is converted to CO in vivo through the reaction of P450 cytochromes (8,9). We examined temporal changes in percentages of carboxyhemoglobin (HbCO) contents in venous blood samples collected from rats undergoing the current protocols for the dichloromethane administration according to the previous method (8). The testes removed 12 hours after the CdCl 2 administration was used to determine contents of microsomal P450 cytochromes and to examine apoptosis.…”

Section: Methodsmentioning

confidence: 99%

Leydig cell–derived heme oxygenase-1 regulates apoptosis of premeiotic germ cells in response to stress

Ozawa¹,

Goda²,

Makino³

et al. 2002

J. Clin. Invest.

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Stress-induced downregulation of spermatogenesis remains poorly understood. This study examined the induction of heme oxygenase-1 (HO-1), a carbon monoxide-generating inducible enzyme, in modulation of spermatogenesis. Rats were exposed to cadmium chloride (CdCl 2 ), a stressor causing oligozoospermia, and HO-1-induction was monitored by following HO isozyme expression. CdCl 2 -treated testes increased HO-1 activity and suppressed microsomal cytochromes P450, which are required for steroidogenesis. CdCl 2 -elicited HO-1 occurred mostly in Leydig cells and coincided with CO generation, as judged by bilirubin-IXα immunoreactivity. Under these circumstances, germ cells in peripheral regions of seminiferous tubules exhibited apoptosis; laser flow cytometry revealed that these apoptotic cells involve diploid and tetraploid germ cells, suggesting involvement of spermatogonia and primary spermatocytes in CdCl 2 -elicited apoptosis. Pretreatment with zinc protoporphyrin-IX, an HO inhibitor, but not copper protoporphyrin-IX, which does not block the enzyme, attenuated the CdCl 2 -induced apoptosis. Such antiapoptotic effects of zinc protoporphyrin-IX were repressed by supplementation of dichloromethane, a CO donor. Upon CdCl 2 -treatment, both Sertoli cells and the germ cells upregulated Fas ligand; this event was also suppressed by zinc protoporphyrin-IX and restored by dichloromethane. Thus, Leydig cells appear to use HO-1-derived CO to trigger apoptosis of premeiotic germ cells and thereby modulate spermatogenesis under conditions of stress.

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“…Earlier it has been shown that dichloromethane potentiates the toxicity of other organic solvents such as carbon tetrachloride in rats during concomitant treatment (Kim 1997) while styrene metabolism in addition is influenced by several different organic solvents (Ikeda & Hirayama 1978). The effect of styrene on dichloromethane metabolism, especially following in vivo pretreatment of rats, has received less attention.…”

Section: Discussionmentioning

confidence: 99%

In vitro Screening for Metabolic Interactions among Frequently Occurring Binary Mixtures of Volatile Organic Chemicals in Norwegian Occupational Atmosphere

Mortensen

Osvoll

Woldbæk

et al. 1998

Pharmacology & Toxicology

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Surveys of Norwegian industrial occupational atmosphere between 1983 to 1996, have identified the 12 most frequent occurring binary combinations of volatile organic chemicals. These combinations were tested in vitro for mutual inhibition or enhancement of metabolism by the head space vial equilibration technique with liver S9 obtained from in viva untreated or pretreated (with the binary mixture) rats. The in vitro system responded to in vivo pretreatment by increasing the metabolic rate of several potentially toxic organic chemicals such as toluene, xylene, styrene, and dichloromethane. In untreated liver S9, the metabolism of several of the tested binary pairs was inhibited when coexposed in vitro to their most prevalent follower as shown for instance for ethanol (with ethyl acetate), dichloromethane (with styrene) and mutually between toluene and xylene. This inhibitory effect disappeared, however, for several of the solvents when combined with the in vivo induced liver S9, a situation which may be the most relevant for occupational exposure. It is concluded that several metabolic interactions occur between low-molecular weight volatile chemicals found in occupational air. These are both inductive and inhibitory in nature and a further mechanistic evaluation including a higher number of differentiated dosage levels, must be performed before a possible health hazard can be confirmed or rejected for the investigated combinations.

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Dichloromethane Potentiation of Carbon Tetrachloride Hepatotoxicity in Rats

Cited by 9 publications

References 2 publications

Micronuclei in Bone Marrow and Liver in relation to Hepatic Metabolism and Antioxidant Response due to Coexposure to Chloroform, Dichloromethane, and Toluene in the Rat Model

Micronuclei in Bone Marrow and Liver in relation to Hepatic Metabolism and Antioxidant Response due to Coexposure to Chloroform, Dichloromethane, and Toluene in the Rat Model

Leydig cell–derived heme oxygenase-1 regulates apoptosis of premeiotic germ cells in response to stress

In vitro Screening for Metabolic Interactions among Frequently Occurring Binary Mixtures of Volatile Organic Chemicals in Norwegian Occupational Atmosphere

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