Protein Information

Name cytochrome P450 (protein family or complex)
Synonyms cytochrome P450; cytochrome P 450; CYP450; CYP 450

Compound Information

Name methylene chloride
CAS dichloromethane

Reference List

PubMed Abstract RScore(About this table)
8671747 Doherty AT, Ellard S, Parry EM, Parry JM: An investigation into the activation and deactivation of chlorinated hydrocarbons to genotoxins in metabolically competent human cells. Mutagenesis. 1996 May;11(3):247-74.

The MCL-5 and h2E1 cell lines have in addition shown the capacity to produce metabolites in the presence of methylene chloride, carbon tetrachloride, 1,2,3-trichloropropane, tetrachloroethylene, toluene and n-hexane, wich yield elevated micronucleus frequencies compared with the parental cell line AHH-1.
The methodology used has shown the ability of metabolically competent cell lines expressing cDNAs encoding the cytochrome P450 isoenzymes to metabolize halogenated hydrocarbons to genotoxic species, including both clastogens and aneugens.
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16719384 Waxman DJ, Chang TK: Thin-layer chromatography analysis of human CYP3A-catalyzed testosterone 6beta-hydroxylation. Methods Mol Biol. 2006;320:133-41.


Testosterone and other steroid hormones have been studied as prototypic examples of endogenous substrates for hepatic cytochrome P450 (P450) enzymes.
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10574192 Testino SA Jr, Ozarowski J, Thurston AW, Arrendale RF, Patonay G: Determination of testosterone and 6beta-hydroxytestosterone by gas chromatography-selected ion monitoring-mass spectrometry for the characterization of cytochrome p450 3A activity. J Chromatogr B Biomed Sci Appl. 1999 Oct 29;734(1):73-81.

Testosterone and its metabolites are extracted from the incubation mixture in a single step with methylene chloride.
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1375920 Foster JR, Green T, Smith LL, Lewis RW, Hext PM, Wyatt I: Methylene chloride--an inhalation study to investigate pathological and biochemical events occurring in the lungs of mice over an exposure period of 90 days. Fundam Appl Toxicol. 1992 Apr;18(3):376-88.

This suggested that with time the lung (Clara cell) has developed tolerance to MC possibly due to the inactivation of a cytochrome P450 isozyme.
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1871779 Pankow D, Matschiner F, Weigmann HJ: Influence of aromatic hydrocarbons on the metabolism of dichloromethane to carbon monoxide in rats. Toxicology. 1991;68(1):89-100.


In conclusion, it seems that the stimulation or inhibition of the COHb formation after DCM caused by pretreatment with or by simultaneous administration of the aromatic solvents is due to the induction of cytochrome P-450 IIE1 or to competition between DCM and the aromatic solvent on this isozyme of cytochrome P-450.
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8079349 Andersen ME, Clewell HJ 3rd, Mahle DA, Gearhart JM: Gas uptake studies of deuterium isotope effects on dichloromethane metabolism in female B6C3F1 mice in vivo. Toxicol Appl Pharmacol. 1994 Sep;128(1):158-65.

In common with a diverse group of low-molecular-weight volatile substrates, dichloromethane (DCM; methylene chloride) is a high-affinity, low-capacity substrate for oxidation by several cytochrome P450 isoenzymes in vivo.
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7624875 Manno M, Tolando R, Ferrara R, Rezzadore M, Cazzaro S: Suicidal inactivation of haemoproteins by reductive metabolites of halomethanes: a structure-activity relationship study. Toxicology. 1995 Jun 26;100(1-3):175-83.

Human haemoglobin (Hb), methaemalbumin (MHA) or rat liver microsomal cytochrome P-450 (P-450) were incubated anaerobically at microM concentrations with 1 mM carbon tetrachloride (CCl4), trichlorobromomethane (CCl3Br), chloroform (CHCl3) or methylene chloride (CH2Cl2) in presence of 1 mM sodium dithionite as the reducing agent.
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2549914 Ottenwalder H, Jager R, Thier R, Bolt HM: Influence of cytochrome P-450 inhibitors on the inhalative uptake of methyl chloride and methylene chloride in male B6C3F1 mice. Arch Toxicol Suppl. 1989;13:258-61.
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3341052 Takano T, Miyazaki Y: Metabolism of dichloromethane and the subsequent binding of its product, carbon monoxide, to cytochrome P-450 in perfused rat liver. Toxicol Lett. 1988 Jan;40(1):93-6.

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8889796 Kim SK, Kim YC: Effect of a single administration of benzene, toluene or m-xylene on carboxyhaemoglobin elevation and metabolism of dichloromethane in rats. J Appl Toxicol. 1996 Sep-Oct;16(5):437-44.


Disulfiram (3.4 mmol kg-1, p.o.) blocked COHb elevation completely, suggesting that the metabolic conversion of DCM to CO is mediated by cytochrome P-450 2E1 (P4502E1).
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2567070 Kitchin KT, Brown JL: Biochemical effects of three carcinogenic chlorinated methanes in rat liver. Teratog Carcinog Mutagen. 1989;9(1):61-9.

Three chlorinated methanes, carbon tetrachloride, chloroform, and methylene chloride, known to cause liver tumors in rodents, were given by oral gavage to adult female rats both 21 h and 4 h before sacrifice.
Then hepatic DNA damage, ornithine decarboxylase (ODC), cytochrome P-450, glutathione content, and serum alanine aminotransferase (SGPT) activity assays were performed.
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8067899 Pankow D, Damme B, Schror K: Acetylsalicylic acid--inducer of cytochrome P-450 2E1? . Arch Toxicol. 1994;68(4):261-5.

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9654249 Rodriguez-Arnaiz R: Biotransformation of several structurally related 2B compounds to reactive metabolites in the somatic w/w+ assay of Drosophila melanogaster. Environ Mol Mutagen. 1998;31(4):390-401.


The latter have high cytochrome P450-dependent bioactivation capacities.
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8971132 Edwards DJ, Bellevue FH 3rd, Woster PM: Identification of 6',7'-dihydroxybergamottin, a cytochrome P450 inhibitor, in grapefruit juice. Drug Metab Dispos. 1996 Dec;24(12):1287-90.

Grapefruit juice was extracted into methylene chloride and chromatographed by HPLC, and the effect of the HPLC eluent on CYP3A activity was assessed by measuring 6beta-hydroxytestosterone formation in rat liver microsomes.
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8079362 Foster JR, Green T, Smith LL, Tittensor S, Wyatt I: Methylene chloride: an inhalation study to investigate toxicity in the mouse lung using morphological, biochemical and Clara cell culture techniques. Toxicology. 1994 Aug 12;91(3):221-34.

Both cytochrome P-450 (CYP)- and glutathione S-transferase (GST)-dependent metabolism of MC are known to occur.
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1490123 Pankow D, Weise M, Hoffmann P: Effect of isoniazid or phenobarbital pretreatment on the metabolism of dihalomethanes to carbon monoxide. Pol J Occup Med Environ Health. 1992;5(3):245-50.


The data indicate that the oxidative metabolism of dihalomethanes to carbon monoxide is mainly catalyzed by cytochrome P-450 IIE1 and that the DCM-evoked COHb formation seems to be a method of testing whether a chemical is an inducer of this form of cytochrome P-450 in vivo.
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1963733 Adams JS, Beeker TG, Hongo T, Clemens TL: Constitutive expression of a vitamin D 1-hydroxylase in a myelomonocytic cell line: a model for studying 1,25-dihydroxyvitamin D production in vitro. J Bone Miner Res. 1990 Dec;5(12):1265-9.

On normal-phase HPLC, this metabolite cochromatographed with authentic 1,25-(OH) 2D3 in both hexane- and methylene chloride-based solvent systems.
This reaction was inhibited by ketoconazole, a recognized inhibitor of cytochrome P450 mixed-function oxidases including the authentic, renal 25-OHD3 1-hydroxylase.
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8806840 Kim C, Manning RO, Brown RP, Bruckner JV: Use of the vial equilibration technique for determination of metabolic rate constants for dichloromethane. Toxicol Appl Pharmacol. 1996 Aug;139(2):243-51.

In the current study, DCM appeared to be metabolized preferentially by cytochrome P450 IIE1, since substrates (e.g., pyrazole, ethanol, and glycerol) for this isozyme completely inhibited DCM metabolism.
Metabolism of methylene chloride, or dichloromethane (DCM), plays a key role in determining the kinetics and carcinogenicity of the halocarbon.
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9657237 Aravagiri M, Marder SR, Wirshing D, Wirshing WC: Plasma concentrations of risperidone and its 9-hydroxy metabolite and their relationship to dose in schizophrenic patients: simultaneous determination by a high performance liquid chromatography with electrochemical detection. Pharmacopsychiatry. 1998 May;31(3):102-9.

The ratio of RSP/9-OH-RSP concentrations suggested that three of the patients may have deficiency in cytochrome P450 enzyme CYP 2D6.
Both compounds were isolated from plasma by a simple one-step liquid-liquid extraction with 15% methylene chloride in pentane.
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17620348 Kim SN, Seo JY, Jung da W, Lee MY, Jung YS, Kim YC: Induction of hepatic CYP2E1 by a subtoxic dose of acetaminophen in rats: increase in dichloromethane metabolism and carboxyhemoglobin elevation. Drug Metab Dispos. 2007 Oct;35(10):1754-8. Epub 2007 Jul 9.


This is the first report that APAP can increase cytochrome P450 (P450)-mediated hepatic metabolism and the resulting toxicity of a xenobiotic in the whole animal.
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1361146 Manno M, Rugge M, Cocheo V: Double fatal inhalation of dichloromethane. Hum Exp Toxicol. 1992 Nov;11(6):540-5.


However, biotransformation of the solvent to toxic metabolites, including carbon monoxide (via oxidative dehalogenation by the cytochrome P450-dependent mixed function oxidase system) or formaldehyde, formic acid, inorganic chloride and carbon dioxide (via the glutathione-S-transferase pathway) may have also contributed significantly to fatal toxicity.
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8055623 Himmelstein MW, Turner MJ, Asgharian B, Bond JA: Comparison of blood concentrations of 1,3-butadiene and butadiene epoxides in mice and rats exposed to 1,3-butadiene by inhalation. Carcinogenesis. 1994 Aug;15(8):1479-86.

BD epoxides were extracted into methylene chloride and quantified by gas chromatography-mass spectrometry.
Metabolic activation of BD to form the putative DNA-reactive metabolites, butadiene monoxide (BMO) and butadiene diepoxide (BDE), is mediated by cytochrome P450.
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9073595 Wirkner K, Damme B, Poelchen W, Pankow D: Effect of long-term ethanol pretreatment on the metabolism of dichloromethane to carbon monoxide in rats. Toxicol Appl Pharmacol. 1997 Mar;143(1):83-8.


The reason for the elevated biotransformation of DCM was ascertained by means of the determination of p-nitrophenol and aniline hydroxylation in liver microsomes of rats after long-term ETOH treatment to be an increase in cytochrome P450-dependent enzyme activities.
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8080088 Rodrigues AD, Kukulka MJ, Surber BW, Thomas SB, Uchic JT, Rotert GA, Michel G, Thome-Kromer B, Machinist JM: Measurement of liver microsomal cytochrome p450 (CYP2D6) activity using [O-methyl-14C] dextromethorphan. Anal Biochem. 1994 Jun;219(2):309-20.

The basis of the assay is the quantitative measurement of [14C] formaldehyde (0.05-4.0 microM) after addition of NaOH to the microsomal incubates and extraction with methylene chloride.
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15501612 Sweeney LM, Kirman CR, Morgott DA, Gargas ML: Estimation of interindividual variation in oxidative metabolism of dichloromethane in human volunteers. Toxicol Lett. 2004 Dec 30;154(3):201-16.


Time-course data for 13 volunteers (10 males, 3 females) exposed to one or more concentrations of DCM (50 ppm, 100 ppm, 150 ppm, or 200 ppm) for 7.5h were used to optimize the maximal rate of hepatic metabolism (V (maxC)) through the cytochrome P450 pathway for each individual.
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9794803 Sherratt PJ, Manson MM, Thomson AM, Hissink EA, Neal GE, van Bladeren PJ, Green T, Hayes JD: Increased bioactivation of dihaloalkanes in rat liver due to induction of class theta glutathione S-transferase T1-1. Biochem J. 1998 Nov 1;335 ( Pt 3):619-30.


Significantly, the hepatic level of cytochrome P-450 2E1, an enzyme which offers a detoxification pathway for dihaloalkanes, was unchanged by the various inducing agents studied.
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8100433 Pankow D, Jagielki S: Effect of methanol or modifications of the hepatic glutathione concentration on the metabolism of dichloromethane to carbon monoxide in rats. Hum Exp Toxicol. 1993 May;12(3):227-31.


It is concluded that cytochrome P450 IIE1 (CYP 2E1) is responsible for the metabolic interaction of both DCM and MET, and MET may be an inducer of CYP 2E1.
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8006098 Yamane M, Abe A, Yamane S: High-performance liquid chromatography-thermospray mass spectrometry of epoxy polyunsaturated fatty acids and epoxyhydroxy polyunsaturated fatty acids from an incubation mixture of rat tissue homogenate. J Chromatogr. 1994 Feb 11;652(2):123-36.


From these results, a highly active cytochrome P450 system or non-enzymic oxidative reactions in aged rat tissue homogenate were suggested.
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8614014 Markiewicz KV, Howie LE, Safe SH, Donnelly KC: Mutagenic potential of binary and complex mixtures using different enzyme induction systems. J Toxicol Environ Health. 1996 Apr 5;47(5):443-51.

Test samples included benzo [a] pyrene (BaP), pentachlorophenol (PCP), a binary mixture of BaP and PCP, two five-component mixtures, a methylene chloride extract of wood preserving waste-amended soil, and a methanol extract of coal gasification waste.
These data demonstrate the relative importance of the various induced cytochrome P-450 isozymes for the metabolism of mutagenic chemicals and complex mixtures.
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