Carcinogenesis. 1990 Dec;11(12):2239-43.  

Roles of cytochrome P450IIE1 in the dealkylation and denitrosation of
N-nitrosodimethylamine and N-nitrosodiethylamine in rat liver microsomes.

Yoo JS, Ishizaki H, Yang CS.

Department of Chemical Biology and Pharmacognosy, College of Pharmacy, Rutgers
University, Piscataway, NJ 08855-0789.

N-Nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) are widely
occurring nitrosamines and require enzyme-catalyzed activation for their
carcinogenic actions. The low Km forms of the enzyme are generally considered to
be important in the activation of environmental carcinogens. In this work we
examined the role of cytochrome P450IIE1--a constitutive enzyme that is also
inducible by acetone, ethanol, fasting and other factors--in catalyzing the
dealkylation and denitrosation of these two carcinogens. The experimentally
determined Km value of NDMA demethylase depended upon the experimental
conditions and was lower when lower protein concentrations were used. Low Km
values of 15-20 microM were observed for NDMA demethylase with different
preparations of microsomes. In the deethylation of NDEA, a low Km of
approximately 40 microM was observed for both control and acetone-induced
microsomes. Immunoinhibition studies indicated that P450IIE1 was responsible for
almost all the low Km NDMA demethylase activity in acetone-induced microsomes
and greater than 80% in control microsomes. This enzyme was also responsible for
about three-quarters of the low Km NDEA deethylase activity in acetone-induced
microsomes and about half in control microsomes. The denitrosation of NDMA and
NDEA was inhibited to approximately the same extents as the dealkylation
reactions under different experimental conditions, suggesting the involvement of
the same enzyme and perhaps a common initial intermediate in these two types of
reactions. The relevance of this work and its relationship to related
information in the literature are discussed.

PMID: 2265475 [PubMed - indexed for MEDLINE]