Oxidation of N,N-dimethylformamide and N,N-diethylformamide by human liver microsomes and human recombinant P450s.
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.
Amato
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Laboratory of Genetic and Biochemical Toxicology, Istituto di Mutagenesi e Differenziamento-C.N.R., via Moruzzi- Area della Ricerca, 56100 Pisa, Italy.
Grasso
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Longo
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Gervasi
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D018929:Cell Culture Techniques; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004126:Dimethylformamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D004790:Enzyme Induction; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008862:Microsomes, Liver; D010084:Oxidation-Reduction; D012997:Solvents / Q000737:chemistry / Q000378:metabolism*
D017320:HIV Protease Inhibitors; D012997:Solvents; C105334:N,N-diethylformamide; D004126:Dimethylformamide; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1