Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The presence of relatively high levels of prostaglandin H synthase (PHS) in the dog urinary bladder and its ability to mediate the activation of carcinogenic arylamines to DNA-bound products in vitro suggests the involvement of this enzyme in arylamine-induced bladder carcinogenesis. Since the PHS-dependent metabolism of 2-naphthylamine (2-NA) had been shown to yield both ring- and N-oxidation products in vitro, we compared the reactivity of 3H-labeled N-hydroxy-2-naphthylamine (N-OH-2-NA), 2-nitrosonaphthalene, and 2-amino-1-naphthol (2-AN) toward DNA and protein. In the PHS-incubation system, all three derivatives bound at high levels to protein, but only N-OH-2-NA and 2-AN bound appreciably to DNA. Though ring-oxidation has usually been considered a detoxification pathway, the covalent binding of [3H]2-AN to DNA was found to occur readily under aerobic conditions and was enhanced at acidic pH. At pH 5 in air, the reactivity of [3H]2-AN with nucleic acids and protein was in the order: serum albumin greater than tRNA greater than poly G greater than poly C greater than DNA greater than poly A greater than rRNA greater than poly U. Enzymatic hydrolysis of DNA reacted with [3H]2-AN and subsequent analysis by h.p.l.c. indicated the presence of several carcinogen-nucleoside adducts. The major product was characterized as N4-(deoxyguanosin-N2-yl)-2-amino-1,4-naphthoquinoneimine; and two minor products were tentatively identified as N4-(deoxyadenosin-N6-yl)-2-amino-1,4-naphthoquinoneimine and a deoxyguanosin-N2-yl adduct of a naphthoquinoneimine dimer. These adducts accounted for approximately 60% of the total DNA binding obtained by incubation of [3H]2-NA with PHS in vitro and for approximately 20% of the [3H]2-NA bound to dog urothelial DNA in vivo. The remaining adducts were identical to those previously reported as products of the reaction of N-OH-2-NA with DNA. These results suggest that a minor proportion of the DNA adducts found in vivo may be formed by PHS-activation of 2-NA in the target tissue. Furthermore, the reactivity of 2-AN with cellular nucleophiles, presumably through formation of 2-imino-1-naphthoquinone or a protonated 4-naphthocarbenium ion, indicates that ring-oxidation products of arylamines and of other carcinogenic aryl compounds should be evaluated as proximate carcinogenic metabolites.
Carcinogenesis 1985 Sep
PMID:DNA adducts formed by ring-oxidation of the carcinogen 2-naphthylamine with prostaglandin H synthase in vitro and in the dog urothelium in vivo. 392 86

The hepatic metabolism of arylamine bladder carcinogens to N-hydroxy arylamine N-glucuronides, their excretion in the urine, and their subsequent acidic hydrolysis to highly carcinogenic and reactive N-hydroxy arylamines have been proposed as essential steps in arylamine-induced urinary bladder carcinogenesis. In this study, alteration of urinary pH, inhibition of metabolic sulfation, and blockage of biliary disposition were shown to profoundly affect the urinary excretion of the probable ultimate bladder carcinogen, N-hydroxy-2-naphthylamine (N-HO-2-NA) and its N-glucuronide conjugate. The normal pH of rat urine (6.7) was altered to 5.7 or 7.7 by administration of NH4Cl or NaHCO3 in the drinking water. Subsequent treatment with either 2-naphthylamine (2-NA) or 2-nitronaphthalene (2-NN) resulted in increased urinary levels of free N-HO-2-NA (relative to its N-glucuronide) in acidic urines and decreased relative amounts of free N-HO-2-NA in alkaline urines. In addition, 2-NN yielded 5--10-fold greater levels of urinary N-HO-2-NA and its N-glucuronide than rats given 2-NA; and 2-NA was not detected as a urinary metabolite of 2-NN. Some 12 additional metabolites of 2-NA and 2-NN were also found. Of these, 2-amino-1-naphthol and its sulfate and glucuronide conjugates were quantitated. From these data, 2-NA and 2-NN appear to share common metabolic pathways which yield free N-HO-2-NA as a putative ultimate urinary bladder carcinogen. Pentachlorophenol, a known inhibitor of hepatic sulfotransferases, was shown to cause a 2--3-fold increase in the urinary levels of N-HO-2-NA N-glucuronide and N-HO-2-NA from 2-NA-treated rats. Similarly, inhibition of the biliary excretion of 2-NA by bile duct ligation resulted in a 6-fold increase in total urinary N-HO-2-NfA. Furthermore, analyses of bile revealed that substantial amounts of N-HO-2-NA N-glucuronide, but not free N-HO-2-NA, were present. The role of urinary versus biliary excretion of N-hydroxy arylamines in relation to bladder and colon carcinogenesis is discussed.
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PMID:Alteration of urinary levels of the carcinogen, N-hydroxy-2-naphthylamine, and its N-glucuronide in the rat by control of urinary pH, inhibition of metabolic sulfation, and changes in biliary excretion. 625 2