Kinetics and enzyme involvement in the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in microsomes of rat lung and nasal mucosa.
The rat lung and nasal cavity are two target organs for carcinogenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In order to characterize further the enzymes involved in the bioactivation of NNK, detailed kinetic and inhibitory studies were conducted with rat lung and nasal mucosa microsomes, and the results were compared with previous studies. The enzymes in rat lung microsomes catalyzed the alpha-hydroxylation, pyridine N-oxidation and carbonyl reduction of NNK. The apparent Km for the formation of the NNK-derived keto aldehyde, NNK-N-oxide, the NNK-derived keto alcohol and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol were 28.8, 10.4, 7.0 and 178.1 microM respectively. In rat nasal microsomes, alpha-hydroxylation was the predominant pathway and the rate was approximately 200 times higher than that in lung microsomes. The apparent Kms for keto aldehyde and keto alcohol formation in rat nasal microsomes were 9.6 and 10.1 microM respectively. The cytochrome P450 inhibitors metyrapone and carbon monoxide markedly inhibited the metabolism of NNK in both rat lung and nasal microsomes. In rat lung microsomes, alpha-naphthoflavone and monospecific antibodies against P450s 1A2, 2A1 and 2B1 inhibited the formation of keto aldehyde by 39, 46, 64 and 23% respectively. In rat nasal microsomes, alpha-naphthoflavone and antibodies against P450s 1A2, 2A1 and 3A inhibited the metabolism of NNK by 80, 35, 20 and 14% respectively. The results indicate that cytochromes P450 play a major role in the metabolic activation of NNK in rat lung and nasal microsomes, and that there are tissue-related differences in NNK metabolism.
Smith
T J
TJ
Laboratory for Cancer Research, College of Pharmacy, Rutgers University, Piscataway, NJ 08855-0789.
Guo
Z
Z
Hong
J Y
JY
Ning
S M
SM
Thomas
P E
PE
Yang
C S
CS
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001571:Benzoflavones / Q000494:pharmacology; D002248:Carbon Monoxide / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006900:Hydroxylation; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D008861:Microsomes / Q000378:metabolism*; D009297:Nasal Mucosa / Q000378:metabolism*; D009602:Nitrosamines / Q000493:pharmacokinetics*; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains
D001571:Benzoflavones; D007527:Isoenzymes; D009602:Nitrosamines; C011512:alpha-naphthoflavone; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D002248:Carbon Monoxide; D003577:Cytochrome P-450 Enzyme System; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin; D008797:Metyrapone