Toxicological Sciences, Vol 47, 144-150, Copyright © 1999 by Society of Toxicology
W Volkel, N Wolf, M Derelanko and W Dekant
Acetoxime and methylethyl ketoxime (MEKO) are tumorigenic in rodents,
inducing liver tumors in male animals. The mechanisms of tumorigenicity for
these compounds are not well defined. Oxidation of the oximes to nitronates
of secondary-nitroalkanes, which are mutagenic and tumorigenic in rodents,
has been postulated to play a role in the bioactivation of ketoximes. In
these experiments, we have compared the oxidation of acetoxime and
methylethyl ketoxime to corresponding nitronates in liver microsomes from
different species. The oximes were incubated with liver microsomes from
mice, rats, and several human liver samples. After tautomeric equilibration
and extraction with n- hexane, 2-nitropropane and 2-nitrobutane were
quantitated by GC/MS-NCI (limit of detection of 250 fmol/injection volume).
In liver microsomes, nitronate formation from MEKO and acetoxime was
dependent on time, enzymatically active proteins, and the presence of
NADPH. Nitronate formation was increased in liver microsomes of rats
pretreated with inducers of cytochrome P450 and reduced in the presence of
inhibitors (n-octylamine and diethyldithiocarbamate). Rates of oxidation of
MEKO (Vmax) were 1.1 nmol/min/mg (mice), 0.5 nmol/min/mg (humans), and 0.1
nmol/min/mg (rats). In addition to nitronates, several minor metabolites
were also enzymatically formed (two diastereoisomers of 3- nitro-2-butanol,
2-hydroxy-3-butanone oxime and 2-nitro-1-butanol). Acetoxime was also
metabolized to the corresponding nitronate at rates approximately 50% of
those observed with MEKO oxidation in the three species examined.
2-Nitro-1-propanol was identified as a minor product formed from acetoxime.
No sex differences in the capacity to oxidize acetoxime and MEKO were
observed in the species examined. The observed results show that formation
of sec-nitronates from ketoximes occurs slowly, but is not the only pathway
involved in the oxidative biotransformation of these compounds. Due to the
lack of sex-specific oxidative metabolism, other metabolic pathways or
mechanisms of tumorigenicity not involving bioactivation may be involved in
the sex- specific tumorigenicity of ketoximes in rodents.
ARTICLES
Slow oxidation of acetoxime and methylethyl ketoxime to the corresponding nitronates and hydroxy nitronates by liver microsomes from rats, mice, and humans
Department of Toxicology, University of Wurzburg, Germany.
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