Patients with familial adenomatous polyposis (FAP) and age and sex matched controls were tested for cytochrome P4501A2 (CYP1A2), N-acetyltransferase, and xanthine oxidase activities using caffeine urinary metabolites as a discriminator. FAP patients showed significant underactivity of N-acetyltransferase (which inactivates some carcinogens) and significant overactivity of CYP1A2 (which activates some carcinogens). Xanthine oxidase activity, which can generate free radicals and cause cellular damage, was significantly increased in the FAP patients. All but one of the FAP patients had undergone colectomy. A separate group of six patients was therefore assessed before and at an average time of eight weeks after colectomy. No effect on enzyme activity was seen. The differences in enzyme activities detected in this study could produce an excess of active carcinogenic metabolites in the bile of FAP patients and contribute to the high risk for intestinal cancer in FAP. (Gut 1995; 36: 251-254 Of the FAP patients, six (21%) were smokers, while 11 (20%) of the controls were smokers. All patients were white with normal liver and kidney function. All but one of the FAP patients had undergone colectomy between 1 and 38 years before sampling. All controls had intact colons.To assess the effect of colectomy on enzyme function, five FAP patients and one patient with ulcerative colitis (average age 24 years, range 17-46; 5 males, 1 female) received analysis of N-acetyltransferase, CYP1A2, and xanthine oxidase activity immediately before colectomy and at a mean time of eight weeks (range 6 to 12) after colectomy.Urine samples were collected at two to six hours after the oral administration of a 300 mg tablet of caffeine (FAP patients) or after a caffeine containing beverage (controls), caffeine intake having been shown not to affect the metabolic profiles obtained.6 Patients were not fasted and were not subject to any dietary restrictions. Ethics committee approval was obtained for this study. Urine samples were stored at -20°C and were later analysed as a single batch.7The caffeine metabolites 1-methyluracil (1-MU), 1-methylxanthine (1-MX), 5-acetylamino-6-amino-3-methyluracil (AAMUwhich is the metabolite of 5-acetylamino-6-formylamino-3-methyluracil (AFMU)) were assayed in the urine samples by a modification of the method of Grant et al.
SummaryTo test whether the presence of gastric adenomas (dysplasia) was associated with gastric reflux of duodenal contents, six patients with familial adenomatous polyposis (FAP) who had gastric adenomas and nine matched FAP patients without gastric adenomas underwent scintigraphic duodeno-gastric reflux scanning. Reflux was graded 0-6, where O=no reflux, l=intermittent reflux into antrum only, 2=prolonged reflux into antrum only, 3=intermittent reflux into body, 4=prolonged reflux into body, 5=intermittent reflux into body and fundus, and 6=prolonged reflux into body and fundus. FAP patients with gastric adenomas had more severe reflux (median 6, range 4-6) than did controls (median 3, range 0-6; P=0.009, Mann-Whitney U test). These results are consistent with a role for bile in the development of gastric adenomatous polyps and suggest that bile is involved in the dysplasiacarcinoma sequence.
Patients with familial adenomatous polyposis have an excess risk for adenomas and cancers of the upper and lower gastrointestinal tract. In the upper intestine these lesions occur mainly around the ampulla of Vater and they parallel mucosal exposure to bile. In view of this finding and of evidence that bile acids play a role in colorectal carcinogenesis, biliary bile acid profiles were determined in 29 patients with familial adenomatous polyposis (12 before colectomy, 17 after colectomy) and in 28 patients without familial adenomatous polyposis (all with colons in situ). Patients with familial adenomatous polyposis had a higher total biliary bile acid concentration than the others. The bile of patients with polyposis had a greater proportion of chenodeoxycholic acid and a lower proportion of deoxycholic acid than did the bile of patients without polyposis. The ratio of chenodeoxycholic acid and its metabolite lithocholic acid to cholic acid and its metabolite deoxycholic acid, which is related to subsequent bile acid profiles in the colon, was higher in patients with polyposis. Because bile acids influence cellular proliferation, these findings may be of importance with respect to intestinal adenoma and cancer growth.
Duodenal adenomas occur almost inevitably in patients with familial adenomatous polyposis (FAP) whereas gastric adenomas are rare. FAP patients are also at high risk of duodenal cancer. Within the duodenum, adenomas cluster around the ampulla of Vater, as do the majority of duodenal cancers, suggesting that bile plays a role in tumour development. We therefore tested duodenal bile from 29 postcolectomy FAP patients (27 of whom had duodenal adenomas) and 24 non-FAP patients for mutagenicity, using techniques that detect point mutations in bacteria. Results which appeared to show that FAP bile was more mutagenic than control bile could be accounted for by a feeding effect, elimination of which also eliminated 'mutagenicity'. Under the conditions of our assays we conclude that if bile is an important factor in genesis of duodenal tumours, it does not act by inducing point mutation.
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