Carcinogenesis, Vol 18, 1577-1584, Copyright © 1997 by Oxford University Press
TJ Smith, AM Liao, Y Liu, AB Jones, LM Anderson and CS Yang
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent
tobacco-specific carcinogen in animals. Our previous studies indicated that
there are differences between rodents and humans for the enzymes involved
in the activation of NNK. To determine if the patas monkey is a better
animal model for the activation of NNK in humans, we investigated the
metabolism of NNK in patas monkey lung and liver microsomes and
characterized the enzymes involved in the activation. In lung microsomes,
the formation of 4-oxo-1-(3-pyridyl)-1-butanone (keto aldehyde),
4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone (NNK- N-oxide),
4-hydroxy-1-(3-pyridyl)-1-butanone (keto alcohol), and 4-
(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) was observed, displaying
apparent Km values of 10.3, 5.4, 4.9, and 902 microM, respectively. NNK
metabolism in liver microsomes resulted in the formation of keto aldehyde,
keto alcohol, and NNAL, displaying apparent Km values of 8.1, 8.2, and 474
microM, respectively. The low Km values for NNK oxidation in the patas
monkey lung and liver microsomes are different from those in human lung and
liver microsomes showing Km values of 400-653 microM, although loss of low
Km forms from human tissue as a result of disease, surgery or anesthesia
cannot be ruled out. Carbon monoxide (90%) significantly inhibited NNK
metabolism in the patas monkey lung and liver microsomes by 38-66% and
82-91%, respectively. Nordihydroguaiaretic acid (a lipoxygenase inhibitor)
and aspirin (a cyclooxygenase inhibitor) decreased the rate of formation of
keto aldehyde and keto alcohol by 10-20 % in the monkey lung microsomes.
Alpha-Napthoflavone and coumarin markedly decreased the oxidation of NNK in
monkey lung and liver microsomes, suggesting the involvement of P450s 1A
and 2A6. An antibody against human P450 2A6 decreased the oxidation of NNK
by 12-16% and 22-24% in the patas monkey lung and liver microsomes,
respectively. These results are comparable to that obtained with human lung
and liver microsomes. Coumarin hydroxylation was observed in the patas
monkey lung and liver microsomes at a rate of 16 and 4000 pmol/min/mg
protein, respectively, which was 5-fold higher than human lung and liver
microsomes, respectively. Immunoblot analysis demonstrated that the P450 2A
level in the individual patas monkey liver microsomal sample was 6-fold
greater than in an individual human liver microsomal sample. Phenethyl
isothiocyanate, an inhibitor of NNK activation in rodents and humans,
decreased NNK oxidation in the monkey lung and liver microsomes displaying
inhibitor concentration resulting in 50% inhibition of the activity (IC50)
values of 0.28-0.8 microM and 4.2-6.8 microM, respectively. The results
demonstrate the similarities and differences between species in the
metabolic activation of NNK. The patas monkey microsomes appear to more
closely resemble human microsomes than mouse or rat enzymes and may better
reflect the activation of NNK in humans.
ARTICLES
Enzymes involved in the bioactivation of 4-(methylnitrosamino)-1-(3- pyridyl)-1-butanone in patas monkey lung and liver microsomes
Laboratory for Cancer Research, College of Pharmacy, Rutgers University, Piscataway, NJ 08855, USA.
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