The role of xenobiotic metabolizing enzymes in arylamine toxicity and carcinogenesis: functional and localization studies.
In both animal models and humans, the first and obligatory step in the activation of arylamines is N-hydroxylation. This pathway is primarily mediated by the phase-I enzymes CYP1A1, CYP1A2 and CYP4B1. In the presence of flavonoids such as alpha-naphthoflavone and flavone, both CYP3A4 and CYP3A5 have also been shown to play a minor role in the activation of food-derived heterocyclic amines. The further activation of N-hydroxyarylamines by phase-II metabolism can involve both N, O-acetylation and N, O-sulfonation catalyzed by N-acetyltransferases (NAT1 and NAT2) and sulfotransferases, respectively. Using an array of techniques, we have been unable to detect constitutive CYP1A expression in any segments of the human gastrointestinal tract. This is in contrast to the rabbit where CYP1A1 protein was readily detectable on immunoblots in microsomes prepared from the small intestine. In humans, CYP3A3/3A4 expression was detectable in the esophagus and all segments of the small intestine. Northern blot analysis of eleven human colons showed considerable heterogeneity in CYP3A mRNA between individuals, with the presence of two mRNA species in some subjects. Employing the technique of hybridization histochemistry (also known as in situ hybridization), CYP4B1 expression was observed in some human colons but not in the liver or the small intestine. Hybridization histochemistry studies have also demonstrated variable NAT1 and NAT2 expression in the human gastrointestinal tract. NAT1 and NAT2 mRNA expression was detected in the human liver, small intestine, colon, esophagus, bladder, ureter, stomach and lung. Using a general aryl sulfotransferase riboprobe (HAST1), we have demonstrated marked sulfotransferase expression in the human colon, small intestine, lung, stomach and liver. These studies demonstrate that considerable variability exists in the expression of enzymes involved in the activation of aromatic amines in human tissues. The significance of these results in relation to a role for heterocyclic amines in colon cancer is discussed.
Windmill
K F
KF
Department of Physiology and Pharmacology, University of Queensland, Brisbone, Australia.
McKinnon
R A
RA
Zhu
X
X
Gaedigk
A
A
Grant
D M
DM
McManus
M E
ME
D000588:Amines / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006571:Heterocyclic Compounds / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D017403:In Situ Hybridization; D014018:Tissue Distribution; D015262:Xenobiotics / Q000378:metabolism*
D000588:Amines; D002273:Carcinogens; D006571:Heterocyclic Compounds; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System