title: Deuterium isotope effect on the metabolism of N-nitrosodimethylamine and related compounds by cytochrome P4502E1.
abstract: 1. Deuteration of N-nitrosodimethylamine (NDMA) decreases its carcinogenicity, and produces an isotope effect on its metabolism in vivo. Consistent with these results are the observations that deuteration caused a 5-fold increase in the apparent Km, but not the Vmax for the demethylation and denitrozation of NDMA in acetone-induced rat liver microsomes. These microsomes are a good source of cytochrome P4502E1. 2. For demethylation of Z-[2H3]NDMA and E-[2H3]NDMA, the Km values were indistinguishable, and were between the values for those of NDMA and [2H6]NDMA. Almost all the formaldehyde formed was derived from the non-deuterated methyl group, indicating a lack of stereoselectivity in the demethylation of NDMA. 3. NDMA and [2H6]NDMA displayed apparent Ki values of 59 and 441 microM, respectively, for N-nitrosodiethylamine deethylase, showing an apparent isotope effect of 0.13, and displayed an isotope effect of 0.21 in the Ki values for p-nitrophenol hydroxylase. 4. With acetone and deuterated acetone as inhibitors for p-nitrophenol hydroxylase, the isotope effect on the Ki was 0.11. Similar deuterium isotope effects were also observed with acetone and dimethylformamide as competitive inhibitors for NDMA demethylase. 5. In the microsomal oxidation of ethanol, a deuterium isotope effect of about five was observed in the Vmax/Km when carbon-1 was deuterated, but was not observed in the Vmax. 6. Results illustrate a unique deuterium isotope effect on the Km values of reactions catalysed by P4502E1.
authors.affiliation: Department of Chemical Biology and Pharmacognosy, College of Pharmacy, Rutgers University, Piscataway, NJ 08855-0789.
authors.forename: C S
authors.initials: CS
authors.lastname: Yang
authors.forename: H
authors.initials: H
authors.lastname: Ishizaki
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000494:pharmacology*; D003903:Deuterium / Q000737:chemistry*; D004128:Dimethylnitrosamine / Q000378:metabolism* / Q000493:pharmacokinetics; D007700:Kinetics; D051381:Rats
chemical_list: D003577:Cytochrome P-450 Enzyme System; D003903:Deuterium; D004128:Dimethylnitrosamine