Cytochrome P4501A2: enzyme induction and genetic control in determining 4-aminobiphenyl-hemoglobin adduct levels.
Cytochrome P4501A2 (CYP1A2) activity may be related to bladder cancer risk through metabolic activation of aromatic amines, such as 4-aminobiphenyl (ABP), to reactive intermediates that can form DNA and hemoglobin (Hb) adducts. In the context of a study on smoking and bladder cancer risk, 97 healthy male volunteers were investigated. CYP1A2-dependent N-oxidation activity was measured using a molar ratio of urinary caffeine metabolites [(paraxanthine + 1,7-dimethyluric acid)/caffeine] obtained between the fourth and fifth h after drinking a standardized cup of coffee. N-Oxidation activity was induced by blond tobacco smoke, meat consumption the dinner before the test, or more than four cups of coffee a day. The regular use of medication appeared associated with a decrease in N-oxidation levels. Age and alcohol consumption were not related with CYP1A2 activity. A polymorphic distribution of the CYP1A2 and N-acetyltransferase-2 (determined by the caffeine metabolite ratio 5-acetylamino-6-formylamino-3-methyluracil:1-methylxanthine) phenotypes was examined in relation to susceptibility to ABP-Hb adduct formation. Rapid oxidizers and subjects with the combined slow acetylator-rapid oxidizer phenotype showed the highest ABP-Hb adduct levels at a low smoking dose. Blond tobacco smokers exhibited higher adduct levels compared with black tobacco smokers, after adjustment for the quantity of cigarettes smoked. At the highest levels of smoking exposure, no major difference in ABP-Hb adduct levels was found among the different combinations of CYP1A2 and N-acetyltransferase-2 phenotypes. In a subset of only 45 available samples, no association was seen between the ABP-Hb adduct levels and the glutathione S-transferase M1 genotype.
Landi
M T
MT
EPOCA, Epidemiology Research Center, University of Milan, Italy.
Zocchetti
C
C
Bernucci
I
I
Kadlubar
F F
FF
Tannenbaum
S
S
Skipper
P
P
Bartsch
H
H
Malaveille
C
C
Shields
P
P
Caporaso
N E
NE
Vineis
P
P
D000367:Age Factors; D000428:Alcohol Drinking / Q000009:adverse effects; D000611:Aminobiphenyl Compounds / Q000032:analysis* / Q000378:metabolism; D001191:Arylamine N-Acetyltransferase / Q000096:biosynthesis / Q000235:genetics; D002110:Caffeine / Q000378:metabolism / Q000652:urine; D002273:Carcinogens / Q000032:analysis* / Q000378:metabolism; D003069:Coffee; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D018736:DNA Adducts / Q000032:analysis* / Q000378:metabolism; D004326:Drinking; D004790:Enzyme Induction; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000235:genetics; D006454:Hemoglobins / Q000032:analysis* / Q000378:metabolism; D006801:Humans; D008297:Male; D008460:Meat; D008875:Middle Aged; D010084:Oxidation-Reduction; D010641:Phenotype; D010947:Plants, Toxic; D011110:Polymorphism, Genetic / Q000235:genetics; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D013806:Theophylline / Q000378:metabolism / Q000652:urine; D014026:Nicotiana; D014527:Uric Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000652:urine; D001749:Urinary Bladder Neoplasms / Q000209:etiology
D000611:Aminobiphenyl Compounds; D002273:Carcinogens; D003069:Coffee; D018736:DNA Adducts; D006454:Hemoglobins; C006757:4-biphenylamine; D014527:Uric Acid; D002110:Caffeine; D013806:Theophylline; D019388:Cytochrome P-450 CYP1A2; D001191:Arylamine N-Acetyltransferase; D005982:Glutathione Transferase; C021183:1,7-dimethylxanthine; C053084:1,7-dimethyluric acid