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 major objective of this investigation has been to determine the mechanism by which 3-BHA induces forestomach tumours in rodents. In vitro studies of liver microsomal metabolism of [14C]-3-BHA show binding of metabolites to microsomal protein which could be markedly decreased by addition of L-cysteine. p-Toluenesulphonic acid hydrolysis of the labelled microsomes showed a radioactive peak that co-chromatographed with the major product of the reaction of tert-butylquinone (tert-BuQ) and L-cysteine. In vivo binding of metabolites of [14C]-3-BHA to microsomal protein of the forestomach, glandular stomach and liver was determined. Forestomach microsomal protein contained 14 times as much bound radioactivity as glandular stomach and 12 times as much as liver. HPLC studies showed marked qualitative differences in the distribution of labelled compounds in hydrolysates of microsomes from the three tissues. The forestomach contained peaks not present in the other two tissues. In other studies it was shown that the 3-tert-butyl-5-methoxy-1,2-benzoquinone reacted rapidly with NADPH and NADH. tert-BuQ did so more slowly. Current data suggest that two factors may be of importance for 3-BHA carcinogenesis. The first is thiol depletion resulting from direct binding of quinone metabolites of 3-BHA to tissue thiols. Secondary reactions due to the presence of the quinones could also deplete -SH groups. Such thiol depletion could account for the threshold level existing for 3-BHA carcinogenesis. The second factor is an attack on tissue constituents from reactive metabolites of 3-BHA, as is evident from protein binding, and possibly also from oxygen radicals produced as a result of redox cycling of quinone and hydroquinone metabolites of 3-BHA.
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PMID:Studies related to the mechanism of 3-BHA-induced neoplasia of the rat forestomach. 380 16

[4,5,9,10(-3)H]1-nitropyrene was incubated with NADH- or NADPH-fortified rat liver microsomes under an argon atmosphere. Residual substrate and metabolites were extracted with ethyl acetate and analyzed by high pressure liquid chromatography. Both reduced and oxidized products were formed: namely, 1-aminopyrene, trans-4,5-dihydroxy-4,5-dihydro-1-nitropyrene, and 3-, 6- and 8-hydroxy-1-nitropyrene. When incubations were conducted with rat liver cytosol, only the reduced products 1-nitrosopyrene and 1-aminopyrene were detected. In parallel experiments, [4,5, 9,10-3H]1-nitropyrene was administered to rats by intravenous injection or gavage and the bile was collected. After 4 h, approximately one-third of the intravenously-administered compound appeared in the bile as O-glucuronides of 3-, 6- and 8-hydroxy-1-nitropyrene, the O-glucuronide of trans-4,5-dihydroxy-4,5-dihydro-1-nitropyrene, and unidentified glutathione conjugates. The same metabolites were found in rats treated with 1-nitropyrene by gavage; however, only 10% of the dose appeared in the bile within 12 h. These studies indicate that both nitroreduction and ring oxidation are involved in the hepatic metabolism of 1-nitropyrene. The importance of these pathways in the etiology of 1-nitropyrene tumorigenesis is discussed.
Carcinogenesis 1985 Feb
PMID:Comparison of the in vitro and in vivo hepatic metabolism of the carcinogen 1-nitropyrene. 383 67

The metabolic N-oxidation, N-acetylation and N-deacetylation of the carcinogen benzidine (BZ) and its N-acetylated metabolites were examined in vitro with rat and mouse liver subcellular fractions. N-Oxidation of N-acetylbenzidine (ABZ) and N,N'-diacetylbenzidine (DABZ) was found to occur with NADPH-, NADH-fortified microsomes, although total oxidation at both nitrogens of ABZ was substantially faster than the N-oxidation of DABZ (four times for the mouse and 48 times for the rat). In both species, N-oxidation of ABZ to the arylhydroxylamine, N'-hydroxy-N-acetylbenzidine (N'-OH-ABZ), was somewhat faster than the formation of the arylhydroxamic acid, N-hydroxy-N-acetylbenzidine (N-OH-ABZ). N-Acetylation of BZ and ABZ by liver cytosol was quite efficient for both species (0.7-2.9 nmol/min/mg cytosolic protein), and these rates were found to be 3-10 times faster than their corresponding rates of N-oxidation. N-Deacetylation of ABZ and DABZ by mouse liver microsomes occurred at a rate that was comparable with N-acetylation; while N-deacetylation by rat liver microsomes was relatively slow, only 1-2% of the rate of N-acetylation. In the case of N-hydroxylated derivatives, N-OH-ABZ and N'-OH-ABZ, hepatic cytosolic N-acetylation by both rats and mice to form N-OH-DABZ was quite rapid (0.5-1.9 nmol/min/mg cytosol protein). Hepatic microsomal deacetylation of N-OH-DABZ also occurred with both species and was 2-4 times the rate of N-acetylation. These studies indicate that a significant concentration of potentially electrophilic monoacetylated N-oxidized metabolites may accumulate within the liver cell, and that they may serve as intermediates in the synthesis of the highly toxic metabolite, N-OH-DABZ. A major metabolic pathway for the formation of N-OH-DABZ is proposed as: BZ----ABZ----N'-OH-ABZ----N-OH-DABZ. The activation of N-OH-DABZ by cytosolic N,O-acyltransferase and N'-OH-ABZ by cytosolic sulfotransferase and O-acetyltransferase (acetyl CoA-dependent binding to DNA) were also examined. N-OH-DABZ N,O-acyltransferase and N'-OH-ABZ O-acetyltransferase were found to be significant pathways for rat and mouse liver, respectively. In addition, the DNA adduct formed from N-OH-DABZ in the presence of partially-purified rat hepatic N,O-acyltransferase was shown to be N'-(deoxyguanosin-8-yl)-N-acetylbenzidine, which is identical to that formed in rat liver in vivo and in the direct reaction of N'-OH-ABZ with DNA in vitro under acidic conditions.(ABSTRACT TRUNCATED AT 400 WORDS)
Carcinogenesis 1985 Jul
PMID:Hepatic N-oxidation, acetyl-transfer and DNA-binding of the acetylated metabolites of the carcinogen, benzidine. 401 76

To improve identification of preneoplastic bladder cancer cells, we have studied two enzyme histochemical changes in bladder tumors induced in male Fisher 344 rats by the carcinogen N-butyl-N-(4-hydroxybutyl)-nitrosamine. In early areas of focal nodular hyperplasia there was a dramatic increase in staining for NADH:menadione oxidoreductase (diaphorase)activity. In nonfocal areas as well, there were many individual cells with intense staining, while the controls were of uniform moderate staining. Large papillomas and carcinomas often showed heterogeneous staining. gamma-Glutamyltranspeptidase (GGT) was absent from normal urothelium and from all tumors except the most advanced carcinomas and large papillomas. In old, carcinogen-exposed animals, GGT activity was seen in the luminal surface of tumors and in the interlesion urothelium. In newborn rats and in rats with regenerative hyperplasia following wounding of the urothelium, the diaphorase staining was less than that in the untreated adult. Our findings suggest that increased diaphorase activity may serve to identify early islands of carcinogen-induced, enzymatically altered bladder cells, while GGT will not.
Carcinogenesis 1982
PMID:Histochemistry of NADH diaphorase and gamma-glutamyltranspeptidase in rat bladder tumors. 612 24

The cytotoxic effect of 4-nitroquinoline-1-oxide (4NQO) on cultured Chinese hamster cells was drastically reduced by the presence of caffeine (0.2-1 mM). Caffeine, however, did not reduce the cytotoxicity of 4-hydroxyaminoquinoline-1-oxide (4HAQO), an active metabolite of 4NQO. The 105 000 g supernatant from the cell homogenate could catalyze the conversion of 4NQO to 4HAQO in the presence of NADPH or NADH as a hydrogen donor. This enzyme activity was strongly inhibited by caffeine (0.1-10 mM) or dicumarol (10(-8)-10(-6) M), an inhibitor of DT diaphorase (E.C.1.6.99.2). Dicumarol also reduced the cytotoxicity of 4NQO. These results clearly suggest that caffeine inhibits the conversion step of 4NQO to 4HAQO, resulting in a decrease in the cytotoxicity of 4NQO. Furthermore, the frequency of 6-thioguanine-resistant mutation by 4NQO was also strongly reduced by the presence of caffeine (1 mM) in cultured Chinese hamster cells, being consistent with the results of cytotoxicity.
Carcinogenesis 1984 Mar
PMID:Caffeine inhibition of the metabolic activation of a carcinogen, 4-nitroquinoline-1-oxide, in cultured Chinese hamster cells. 620 Feb 48

The effects of 12-O-tetradecanoylphorbol-13-acetate (TPA), all trans-retinoic acid (RA), 5-azacytidine (5-AC), and phenobarbital (PB) on the activities of seven enzymes and/or isozymes of a diploid rat liver epithelial cell line have been studied. At 0.1 microgram/ml, TPA depressed the specific activities of lactate dehydrogenase and gamma-glutamyl transpeptidase, whereas 2 mM PB depressed gamma-glutamyl transpeptidase and alkaline phosphatase. At 0.01 microgram/ml, RA markedly depressed the activity of NADH-diaphorase and lactate dehydrogenase but enhanced the activity of alkaline phosphatase. Only 2 microM 5-AC caused the most significant shift of lactate dehydrogenase isozyme toward the "muscle"-type isozyme. Histochemical studies revealed that PB and 5-AC induced focal areas of cells with glycogen deposits, but no significant changes in either ultrastructure or alpha-fetoprotein and albumin immunohistochemical staining pattern were observed to suggest hepatocytic differentiation. Although none of the enzymatic changes could be consistently correlated with the effects of these biological modifiers on the cellular growth rate, the effect of RA on NADH-diaphorase, lactate dehydrogenase, and alkaline phosphatase activities was the opposite of the changes observed during carcinogenesis of these rat liver epithelial cells by multiple treatments with N-methyl-N'-nitro-N-nitrosoguanidine. The depression of gamma-glutamyl transpeptidase activity by PB is contradictory to that observed histochemically in hepatocytes in vivo, but such discrepancy may be related to the differences in cell type, growth conditions, or duration of exposure.
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PMID:Biochemical effects of 12-O-tetradecanoylphorbol-13-acetate, retinoic acid, phenobarbital, and 5-azacytidine on a normal rat liver epithelial cell line. 620 84

The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) influences neither the State 3 nor the State 4 respiration in rat liver mitochondria. The respiratory control and ADP/O ratio were also unaffected by TPA. The oligomycin-sensitive ATPase activity in submitochondrial particles remained unaltered upon TPA addition, whereas the NADH oxidase activity was slightly inhibited at a very high concentration of TPA (15% decrease at 17 microM TPA). The activity of the superoxide dismutase located to the mitochondria was insensitive to the tumor promoter, and no change in the rate of H2O2 production was found on TPA treatment in vitro. Thus, the mitochondrion is not a likely candidate for the site of action of the tumor promoter.
Carcinogenesis 1983
PMID:Oxygen uptake, ATPase activity, and superoxide dismutase activity in isolated rat liver mitochondria are not influenced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate. 622 26

The effects of treating lactating rats with 3-methylcholanthrene (3-MC) or beta-naphthoflavone (beta-NF) (three i.p. injections of 20 or 40 mg compound/kg of body weight) on hepatic microsomal enzymes of their suckling young were examined. This treatment had no apparent effect on the contents of cytochromes P-450 and b5 or on the activities of NADH- and NADPH-cytochrome c reductases in hepatic microsomes of the pups. However, these microsomes had 8- and 6-fold increased capacities for hydroxylations of benzo[a]pyrene (B[a]P) and N-2-fluorenylacetamide (2-FAA) respectively. These increases were about 5-fold greater in the hepatic microsomes of the dams, in which they were inhibited by 0.1 mM alpha-naphthoflavone (alpha-NF) in vitro 72-81 and 89-95% and by 0.1 mM beta-NF in vitro 12-41 and 60-76% respectively. In the pups, the induced activities were also inhibited, whereas the basal hydroxylations of B[a]P and 2-FAA were stimulated by alpha-NF 2.7- and 5.0-fold and by beta-NF 1.4- and 2.4-fold respectively. The inhibition of the induced hydroxylations by alpha-NF and beta-NF may be explained by their higher affinities (Ks, 0.14 and 0.28 microM, respectively) than those of B[a]P and 2-FAA (Ks, 4.4 to 8.8 and 2.4 to 3.1 microM, respectively) for cytochrome P-450. Whereas beta-NF gave a type I binding spectrum, alpha-NF gave a spectrum composed of type I and reverse-type I elements. Analysis of metabolites of 2-FAA showed differences in their type and amounts formed by hepatic microsomes of beta-NF-treated lactating rats and their pups. Thus, in the dams the formation of 1-, 3-, 5-, 7-, 9- and N-hydroxy-2-FAA was increased by 9-, 30-, 40-, 5-, 20- and 5-fold respectively. In the pups, the formation of 1-, 3-, 5-, 7- and N-hydroxy-2-FAA was increased by 2-, 30-, 18-, 4- and 27-fold respectively. All these increased hydroxylations were inhibited by 0.1 mM alpha-NF in vitro. In the hepatic microsomes of pups from the corn oil-treated dams, alpha-NF stimulated all ring-hydroxylations, but not N-hydroxylation of 2-FAA. The results support earlier findings that microsomal enzymes differ in immature and mature rat liver and suggest that N-hydroxylation of 2-FAA, the activation required for carcinogenesis, and specific ring-hydroxylations are catalyzed by different cytochrome P-450 isozymes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Modifications of carcinogen metabolism in hepatic microsomes of suckling young by 3-methylcholanthrene or beta-naphthoflavone administered to lactating rats. 631 79

The reduction of N-nitrosobis(2-oxopropyl)amine (BOP) and N-nitroso(2-oxopropyl)propylamine (NOPPA) by hepatic and pancreatic cytosol and microsomes from Syrian golden hamsters and Sprague-Dawley rats has been examined. All hepatic fractions reduced both substrates, although the activity depended on the fraction tested and the cofactor employed (NADH or NADPH). Generally, hamster hepatic fractions contained higher activity than the rat hepatic fractions and BOP was a better substrate than NOPPA. Of the pancreatic fractions, only cytosol exhibited reductase activity. The hamster cytosol was able to utilise both cofactors, but the rat fraction exhibited activity only when NADPH was present. BOP was the better substrate for the pancreatic enzymes and in the presence of NADPH, the rat and hamster activities were about equal. These results suggest that the pancreatic reduction of BOP to HPOP is unlikely to be a significant factor in the species-specific induction of pancreatic cancer by BOP.
Carcinogenesis 1983 Nov
PMID:Enzymatic reduction of beta-ketonitrosamines. 664 Aug 48

Incubation of hepatocarcinogenic aminoazo dye, o-aminoazotoluene (OAT) with rat liver microsomes together with NADPH and NADH yielded N-hydroxy-OAT (I), 4'-hydroxy-OAT (II) and a smaller amount of 2'-hydroxymethyl-3-methyl-4-aminoazobenzene (III). As an artifact 4,4'-bis(o-tolylazo)-2,2' -dimethylazoxybenzene (IV) was also detected in a small quantity. The mutagenicities of these metabolites were assayed by using Salmonella typhimurium TA98 and TA100 together with S-9 prepared from the livers of rats treated with polychlorinated biphenyl mixture (PCB). OAT and III were strongly mutagenic, but only when S-9 was present. In contrast, I was a strong mutagen regardless of the presence or absence of S-9. II and IV were non-mutagenic. The yields of I, II and III from OAT were pronouncedly reduced by addition of cytochrome P-450 inhibitors, especially by a cytochrome P-448 inhibitor 7,8-benzoflavone. Mutagenesis by OAT was also inhibited by addition of 7,8-benzoflavone. Activation of OAT for mutagenesis was enhanced by pretreatment of the donor rats with PCB or 3-methyl-cholanthrene and to a much lesser extent by phenobarbital. These findings suggest that N-hydroxylation of OAT mainly proceeds via catalysis by cytochrome P-448 and that this process is an obligatory step for the activation of OAT. Synthetic methods for the preparation of new azo compounds such as I, IV and 2',3-dimethyl-4-nitrosoazobenzene are described.
Carcinogenesis 1982
PMID:In vitro metabolism of o-aminoazotoluene and mutagenesis of Salmonella by the metabolites. 675 67


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