Effects of 5-methoxypsoralen (5-MOP) on arylamine N-acetyltransferase activity in the stomach and colon of rats and human stomach and colon tumor cell lines.
BACKGROUND
It has been shown that cytochrome P450 enzymes (CYPs) and acetyltransferase can be used as biomarkers of carcinogen-DNA adduct levels and human cancer susceptibility. The gastrointestinal tract is the portal of entry of foreign compounds and presents xenobiotic metabolizing N-acetyltransferase (NAT) and CYPs activities. 5-Methoxypsoralen (5-MOP) has been used in combination with UV radiation in skin photochemotherapy for decades. A number of studies have demonstrated that 5-MOP is inhibitory towards mouse and human CYP isoforms, but investigations on the direct effects on NAT activity in laboratory animals and human cancer cells are limited. The main objective of this study was to document the effects of 5-MOP on the modulation of NAT activities in the stomach and colon of rats and human stomach and colon tumor cell lines.


METHODS
N-Acetylation of 2-aminofluorene (AF) to 2-acetylaminofluorene (AAF) by NAT in the stomach and colon of Sprague-Dawley (SD) rats and in human stomach (SC-M1) and colon (COLO 205) tumor cell lines was investigated.


RESULTS
The data show that the metabolic activity of NAT in the rat colon was higher than that in the rat stomach, and the further metabolism of AAF was slower in the stomach than in the colon. 5-MOP increased the activity of NATand also increased the further metabolism of AAF at 24 h in the rat stomach. In the rat colon, no statistically significant changes caused by 5-MOP were observed in NAT activity, but 5-MOP increased the further metabolism of AAF at 24 to 72 h. 5-MOP decreased the activity of NAT only at 72-h incubation in SC-M1 cells. In COLO 205 cells, however, 5-MOP decreased the activity of NAT between 24 h and 72 h. The optimal concentrations of 5-MOP to induce decreased NAT activity in SC-M1 cells were 0.05 mM to 25 mM. In COLO 205 cells, the data indicate that the higher the concentrations of 5-MOP, the higher the acetylation of AF; a promotion effect of NAT activity occured at a higher dose (50 mM) of 5-MOP and an inhibition effect occured at lower doses (0.05-0.5 mM) of 5-MOP, while concentrations of 5-25 mM of 5-MOP showed no significant difference compared with the control regimen.


CONCLUSIONS
The metabolic activity of NAT in the rat colon was higher than that in the rat stomach, and the results also showed a high degree of correspondence with SC-M1 cells and COLO 205 cells. 5-MOP more efficiently inhibited NAT activity in human stomach and colon tumor cell lines than in the stomach and colon of rats.
Lee
Yi-Min
YM
Department of Medical Technology, Chungtai Institute of Health Sciences and Technology, Taichung, Taiwan, Republic of China. ljlee@chtai.ctc.edu.tw
Wu
Tai-Hsien
TH
D015073:2-Acetylaminofluorene / Q000378:metabolism; D000078223:5-Methoxypsoralen; D000107:Acetylation; D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000032:analysis / Q000378:metabolism*; D045744:Cell Line, Tumor; D003106:Colon / Q000201:enzymology*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D003600:Cytosol / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005449:Fluorenes / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008297:Male; D008730:Methoxsalen / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000201:enzymology*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology
D004791:Enzyme Inhibitors; D005449:Fluorenes; C012177:2-aminofluorene; D000078223:5-Methoxypsoralen; D015073:2-Acetylaminofluorene; D001191:Arylamine N-Acetyltransferase; D008730:Methoxsalen