Metabolism of carcinogenic nitrosamines by rat nasal mucosa and the effect of diallyl sulfide.
Rat nasal cavity is one of the target organs for carcinogenesis induced by N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The present work investigated the metabolism of these nitrosamines by rat nasal microsomes, as well as the possible modulating factors. Microsomes prepared from rat nasal mucosa were efficient in metabolizing these nitrosamines. In general, the metabolism of the nitrosamines was slightly higher in 9-week-old rats than in 4-week-old animals, and there was no sex-related difference. Fasting of rats for 48 h, which is known to induce hepatic cytochrome P450IIE1 and NDMA metabolism, did not increase the nasal metabolism of NDMA, NDEA, or NNK. Pretreatment of rats with acetone, another inducer of hepatic P450IIE1, did not increase the metabolism of NDMA. Furthermore, it decreased the nasal metabolism of NDEA and NNK. Immunoinhibition studies suggest that, in the nasal mucosa, P450IIE1 is only partially responsible for the oxidation of NDMA and other P450 isozymes are responsible for the metabolism of NDEA. A single p.o. pretreatment of male rats with diallyl sulfide (DAS), a component of garlic oil, caused a significant decrease in the oxidative metabolism of NDEA and NNK in rat nasal mucosa. Whereas the nasal metabolism of NDMA was reduced by DAS pretreatment, there was no change in the amount of the nasal microsomal proteins immunoreactive with the antibodies against P450IIE1. The inhibitory effect of DAS on the nasal oxidative metabolism of NDMA, NDEA, and NNK was also observed in experiments in vitro. The results demonstrate the ability of nasal mucosa to metabolically activate these nitrosamines and the inhibition of this process by DAS, suggesting that DAS may be effective in inhibiting the related nasal tumorigenesis.
Hong
J Y
JY
Department of Chemical Biology and Pharmacognosy, College of Pharmacy, Rutgers University, Piscataway, New Jersey 08855-0789.
Smith
T
T
Lee
M J
MJ
Li
W S
WS
Ma
B L
BL
Ning
S M
SM
Brady
J F
JF
Thomas
P E
PE
Yang
C S
CS
D000096:Acetone / Q000494:pharmacology; D000367:Age Factors; D000498:Allyl Compounds; D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D004052:Diethylnitrosamine / Q000378:metabolism*; D004128:Dimethylnitrosamine / Q000378:metabolism*; D005260:Female; D008297:Male; D008861:Microsomes / Q000378:metabolism; D009297:Nasal Mucosa / Q000378:metabolism*; D009602:Nitrosamines / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012737:Sex Factors; D013440:Sulfides / Q000494:pharmacology*
D000498:Allyl Compounds; D002273:Carcinogens; D009602:Nitrosamines; D013440:Sulfides; D000096:Acetone; D004052:Diethylnitrosamine; C038491:allyl sulfide; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D004128:Dimethylnitrosamine