To elucidate the mechanism underlying suppression of
N-nitrosobis(2-oxopropyl)amine (BOP)-induced hamster pancreatic
carcinogenesis by cigarette
smoke (CS), hepatic levels of microsomal
cytochrome P450 (CYP)
enzymes, mutagenic activation of
environmental carcinogens and three types of
uridine diphosphate-
glucuronyltransferase (UDPGT) and sulphotransferase (ST) activities were assayed in male Syrian golden hamsters and F344 rats exposed to CS. Immunoblot analyses of microsomal CYP
proteins revealed induction of constitutive
CYP1A2 (2.6-fold increase) and 2A8 (4.0-fold increase) and induction of
CYP1A1 and constitutive
CYP1A2 (3.9-fold increase) in rats following exposure to CS for 4 weeks using a Hamburg type II smoking machine. CS exposure enhanced mutagenicities of four heterocyclic
amines in the presence of liver S9 in both species, whereas the mutagenicities of
aflatoxin B(1) (AFB(1)), 2-amino-3-methyl-9H-pyrido[2,3-b]
indole (MeAαC) and
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were significantly increased by CS in hamsters but not in rats. However, no CS-induced alterations in the mutagenic activities of other
carcinogens, including BOP and other pancreatic
carcinogens, were observed in either species. Application of several CYP inhibitors revealed that the mutagenic activities of MeAαC, AFB(1) and NNK in the hamster liver S9 were partly associated with CYP2A8, whereas those of the three pancreatic
carcinogens were selectively associated with CYP2B. CS enhanced UDPGT activities towards
4-nitrophenol (4-NP) (1.9- to 2.0-fold) but did not affect those of
bilirubin,
testosterone UDPGTs and three STs in both species. Together with the previous findings that BOP does not induce tumourigenesis in rats and that the glucuronidation of β-oxypropylnitrosamines is higher in rats than in hamsters, suppression of BOP-induced pancreatic
carcinogenesis by CS might be attributed to increased detoxification by 4-NP UDPGT and not decreased CYP2B activation. This is the first demonstration of the induction of
CYP2A protein by CS;
CYP2A protein polymorphisms have been associated with oral and pulmonary
carcinogenesis in smokers.