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Research ArticleArticle

Metabolism of Chloroform in the Human Liver and Identification of the Competent P450s

Simonetta Gemma, Luciano Vittozzi and Emanuela Testai
Drug Metabolism and Disposition March 2003, 31 (3) 266-274; DOI: https://doi.org/10.1124/dmd.31.3.266
Simonetta Gemma
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Luciano Vittozzi
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Emanuela Testai
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Abstract

The oxidative and reductive cytochrome P450 (P450)-mediated chloroform bioactivation has been investigated in human liver microsomes (HLM), and the role of human P450s have been defined by integrating results from several experimental approaches: cDNA-expressed P450s, selective chemical inhibitors and specific antibodies, correlation studies in a panel of phenotyped HLM. HLM bioactivated CHCl3 both oxidatively and reductively. Oxidative reaction was characterized by two components, suggesting multiple P450 involvement. The high affinity process was catalyzed by CYP2E1, as clearly indicated by kinetic studies, correlation with chlorzoxazone 6-hydroxylation (r = 0.837; p < 0.001), and inhibition by monoclonal antihuman CYP2E1 and 4-methylpyrazole. The low affinity phase of oxidative metabolism was essentially catalyzed by CYP2A6. This conclusion was supported by the correlation with coumarin 7-hydroxylase (r = 0.777; p < 0.01), inhibition by coumarin and by the specific antibody, in addition to results with heterologously expressed P450s. Chloroform oxidation was poorly dependent on pO2, whereas the reductive metabolism was highly inhibited by O2. The production of dichloromethyl radical was significant only at CHCl3concentration ≥1 mM, increasing linearly with substrate concentration. CYP2E1 was the primary enzyme involved in the reductive reaction, as univocally indicated by all the different approaches. The reductive pathway seems to be scarcely relevant in the human liver, since it is active only at high substrate concentrations, and in strictly anaerobic conditions. The role of human CYP2E1 in CHCl3 metabolism at low levels, typical of actual human exposure, provides insight into the molecular basis for eventual difference in susceptibility to chloroform-induced effects due to either genetic, pathophysiological, or environmental factors.

Footnotes

  • This work has been partially supported by the Istituto Superiore di Sanità Project no.1181/RI. Preliminary results were presented at the 13th International Symposium on Microsomes and Drug Oxidations; 2000 July 10–14; Stresa-Lago Maggiore, Italy.

  • Abbreviations used are::
    P450
    cytochrome P450
    PL
    phospholipid
    HLM
    human liver microsomes
    Abs
    antibodies
    G6P
    glucose-6-phosphate
    4MPYR
    4-methylpyrazole
    ORP
    orphenadrine
    COU
    coumarin
    TAO
    troleandomycin
    SFN
    sulfaphenazole
    PL-PHOS
    PL-adduct with phosgene
    PL-RAD
    PL-adduct with dichloromethyl radical
    Ch6OH
    chlorzoxazone 6-hydroxylation
    Cou7OH
    coumarin 7-hydroxylation
    • Received July 23, 2002.
    • Accepted November 15, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (3)
Drug Metabolism and Disposition
Vol. 31, Issue 3
1 Mar 2003
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Research ArticleArticle

Metabolism of Chloroform in the Human Liver and Identification of the Competent P450s

Simonetta Gemma, Luciano Vittozzi and Emanuela Testai
Drug Metabolism and Disposition March 1, 2003, 31 (3) 266-274; DOI: https://doi.org/10.1124/dmd.31.3.266

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Research ArticleArticle

Metabolism of Chloroform in the Human Liver and Identification of the Competent P450s

Simonetta Gemma, Luciano Vittozzi and Emanuela Testai
Drug Metabolism and Disposition March 1, 2003, 31 (3) 266-274; DOI: https://doi.org/10.1124/dmd.31.3.266
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