Arch Biochem Biophys. 1985 Oct;242(1):32-40.  

Demethylation and denitrosation of nitrosamines by cytochrome P-450 isozymes.

Tu YY, Yang CS.

Metabolism of nitrosamines was studied in a reconstituted monooxygenase system
composed of cytochrome P-450 isozymes purified from liver microsomes of ethanol-
and phenobarbital-treated rats. The ethanol-induced isozyme (P-450et) was
efficient in catalyzing the demethylation of N-nitrosodimethylamine (NDMA), with
a Km of 2.4 mM and Vmax of 7.2 nmol min-1 nmol P-450(-1), but less active with
N-nitrosomethylbenzylamine and N-nitrosomethylaniline. The phenobarbital-induced
form (P-450b) was ineffective in NDMA metabolism but was active in catalyzing
the demethylation of N-nitrosomethylaniline, with an estimated Km of 0.08 mM and
a Vmax of 7.2 nmol min-1 nmol-1. P-450et also catalyzed the denitrosation of
NDMA with a Km of 13.6 mM and a Vmax of 1.36 nmol min-1 nmol-1. With control
liver microsomes, multiple Km values were observed for the demethylation and
denitrosation of NDMA. Involvement of superoxide radicals in the metabolism of
NDMA was suggested by the action of superoxide dismutase, which inhibited the
denitrosation by 43 to 73% and the demethylation by 13 to 22% in different
monooxygenase systems. The P-450et-dependent NDMA demethylation was strongly
inhibited by 2-phenylethylamine and 3-amino-1,2,4-triazole; these compounds were
previously believed not to be inhibitors of P-450-dependent reactions but were
found to inhibit microsomal NDMA demethylase. The present results establish the
role of P-450 in nitrosamine metabolism and help to clarify some of the previous
confusion in this area of research.

PMID: 4051505 [PubMed - indexed for MEDLINE]