Caffeine phenotyping of cytochrome P4501A2, N-acetyltransferase, and xanthine oxidase in patients with familial adenomatous polyposis.

Abstract

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.

Xanthine Oxidoreductase Is an Endogenous Regulator of Cyclooxygenase-2

“…Other conditions in which XOR activity and COX-2 have been tentatively linked include patients with familial adenomatous polyposis. Polypoid lesions in this disease have been demonstrated to have elevations in XO activity 25 as well as COX-2. 26 Indeed, the COX-2 inhibitor Celecoxib has been approved for treatment of these individuals as a therapy for polyp regression.…”

Polymorphisms in the cytochrome P450 CYP1A2 gene (CYP1A2) in colorectal cancer patients and controls: allele frequencies, linkage disequilibrium and influence on caffeine metabolism

“…[9] in colorectal cancer patients, as well as those from Spigelman et al. [28] in familial adenomatous polyposis (FAP) patients. In both studies, patients had higher CYP1A2 activity using caffeine as a probe than controls, although the difference was only slight in the investigation by Lang et al.…”

Expression of heavy subunit of γ‐glutamylcysteine synthetase (γ‐GCSh) in human colorectal carcinoma

“…24 iNOS catalyzes the conversin of L-arginine to L-citrulline and the liberation of diffusion highly reactive nitric oxide species, an array of unstable chemical forms reminiscent of ROS and characteristic of an oxido-reductive imbalance. 25 (v) In familial adenomatous polyposis (FAP) patients, an increase in the free radical generating enzyme xanthine oxidase 26 and a decrease in antioxidant capacity was found. 27 Moreover, Bras et al 28 reported that prooxidant status (lipid peroxidation) is statistically increased was higher and antioxidant status (ascorbate and catalase activities ) was reduced.…”