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Oxidation of N,N-dimethylformamide and N,N-diethylformamide by human liver microsomes and human recombinant P450s. 2001

G Amato, and E Grasso, and V Longo, and P G Gervasi
Laboratory of Genetic and Biochemical Toxicology, Istituto di Mutagenesi e Differenziamento-C.N.R., via Moruzzi- Area della Ricerca, 56100 Pisa, Italy.

N-N, dimethyl- (DMF) and N-N, diethyl-formamide (DEF) are two hepatotoxic solvents, whose metabolism has not been investigated in humans. To identify the P450 isoforms involved in the microsomal oxidation of these solvents we used (a) 12 human liver samples; (b) human recombinant P450 isoforms (1A1, 1A2, 2B6, 2C10, 2E1, 3A4); (c) chemical and immunological inhibitions. When correlation analyses were performed using enzymatic markers in human liver microsomes, the p-nitrophenol hydroxylation rate significantly correlated (r=0.87) with the dealkylation rate of DMF but not with that of DEF. Among the tested recombinant P450s only 2E1 oxidised DMF, while DEF was oxidised by 2E1, 2C10 and 3A4. 4-Methylpyrazole and anti human 2E1 IgG strongly inhibited the DMF demethylation but only partially the DEF deethylation. These findings indicate that, in the DMF metabolism, the role of 2E1 is crucial and its expression may be an important factor in determining the susceptibility of human to this solvent.

UI MeSH Term Description Entries
D008862 Microsomes, Liver Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough. Liver Microsomes,Liver Microsome,Microsome, Liver
D010084 Oxidation-Reduction A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). Redox,Oxidation Reduction
D003577 Cytochrome P-450 Enzyme System A superfamily of hundreds of closely related HEMEPROTEINS found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (MIXED FUNCTION OXYGENASES). In animals, these P-450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (BIOTRANSFORMATION). They are classified, according to their sequence similarities rather than functions, into CYP gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the CYP1, CYP2, and CYP3 gene families are responsible for most drug metabolism. Cytochrome P-450,Cytochrome P-450 Enzyme,Cytochrome P-450-Dependent Monooxygenase,P-450 Enzyme,P450 Enzyme,CYP450 Family,CYP450 Superfamily,Cytochrome P-450 Enzymes,Cytochrome P-450 Families,Cytochrome P-450 Monooxygenase,Cytochrome P-450 Oxygenase,Cytochrome P-450 Superfamily,Cytochrome P450,Cytochrome P450 Superfamily,Cytochrome p450 Families,P-450 Enzymes,P450 Enzymes,Cytochrome P 450,Cytochrome P 450 Dependent Monooxygenase,Cytochrome P 450 Enzyme,Cytochrome P 450 Enzyme System,Cytochrome P 450 Enzymes,Cytochrome P 450 Families,Cytochrome P 450 Monooxygenase,Cytochrome P 450 Oxygenase,Cytochrome P 450 Superfamily,Enzyme, Cytochrome P-450,Enzyme, P-450,Enzyme, P450,Enzymes, Cytochrome P-450,Enzymes, P-450,Enzymes, P450,Monooxygenase, Cytochrome P-450,Monooxygenase, Cytochrome P-450-Dependent,P 450 Enzyme,P 450 Enzymes,P-450 Enzyme, Cytochrome,P-450 Enzymes, Cytochrome,Superfamily, CYP450,Superfamily, Cytochrome P-450,Superfamily, Cytochrome P450
D004126 Dimethylformamide A formamide in which the amino hydrogens are replaced by methyl groups. N,N-Dimethylformamide,N,N Dimethylformamide
D004790 Enzyme Induction An increase in the rate of synthesis of an enzyme due to the presence of an inducer which acts to derepress the gene responsible for enzyme synthesis. Induction, Enzyme
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D012997 Solvents Liquids that dissolve other substances (solutes), generally solids, without any change in chemical composition, as, water containing sugar. (Grant & Hackh's Chemical Dictionary, 5th ed) Solvent
D017320 HIV Protease Inhibitors Inhibitors of HIV PROTEASE, an enzyme required for production of proteins needed for viral assembly. HIV Protease Inhibitor,Inhibitor, HIV Protease,Inhibitors, HIV Protease,Protease Inhibitor, HIV,Protease Inhibitors, HIV
D018929 Cell Culture Techniques Methods for maintaining or growing CELLS in vitro. Cell Culture,Cell Culture Technique,Cell Cultures,Culture Technique, Cell,Culture Techniques, Cell
D019392 Cytochrome P-450 CYP2E1 An ethanol-inducible cytochrome P450 enzyme that metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Substrates include ETHANOL; INHALATION ANESTHETICS; BENZENE; ACETAMINOPHEN and other low molecular weight compounds. CYP2E1 has been used as an enzyme marker in the study of alcohol abuse. 4-Nitrophenol-2-Hydroxylase,CYP2E1,Dimethylnitrosamine N-Demethylase,CYP 2E1,CYP IIE1,CYPIIE1,Cytochrome P-450 (ALC),Cytochrome P-450 IIE1,Cytochrome P-450-J,Cytochrome P450 2E1,N-Nitrosodimethylamine Demethylase,4 Nitrophenol 2 Hydroxylase,Cytochrome P 450 CYP2E1,Cytochrome P 450 IIE1,Cytochrome P 450 J,Dimethylnitrosamine N Demethylase,N Nitrosodimethylamine Demethylase

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