Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Transport of the renal carcinogen 3-hydroxymethyl-1-([3-(5-nitro-2-furyl)-allydidene]amino) hydantoin (HMN) by the renal cortex and metabolism by the kidney was evaluated. Organic acid and base transport by renal cortical slices was determined using [131I]Hippuran and [14C]tetraethylammonium, respectively. HMN caused a dose-dependent reversible inhibition of [131]Hippuran accumulation but did not alter [14C]tetraethylammonium uptake. By contrast, benzidine inhibited organic base but not acid transport. The decrease in absorbance at 405 nm was used as an index of microsomal metabolism of HMN. Reduced nicotinamide adenine dinucleotide phosphate-dependent metabolism of HMN was not observed with either cortical or medullary microsomes. However, there was prostaglandin endoperoxide synthetase-mediated metabolism of HMN. Specific substrate, cofactor, and inhibitor studies suggest that metabolism occurs by the prostaglandin hydroperoxidase activity of prostaglandin endoperoxide synthetase. At least one product of HMN metabolism was characterized and shown to be different from HMN by its high-pressure liquid chromatographic and ultraviolet spectral properties. The renal mixed-function oxidases system, lipid peroxidation, nitroreduction, and lipoxygenase did not seem to be involved in HMN metabolism. These results are consistent with the hypothesis that the kidney is a site for cooxidative metabolism of chemicals which elicit carcinogenic and nephrotoxic effects in the kidney. Facilitated transport of HMN into renal tissue by the organic acid transport system may explain the greater potential for HMN to elicit renal carcinogenesis compared to other tissues.
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PMID:Transport of the renal carcinogen 3-hydroxymethyl-1-([3-(5-nitro-2-furyl)allydidene]amino) hydantoin by renal cortex and cooxidative metabolism by prostaglandin endoperoxide synthetase. 678 31

Transforming growth factor alpha (TGF-alpha) is a polypeptide closely associated with hepatocyte proliferation in vivo and in vitro. In order to investigate the mechanisms by which TGF-alpha contributes to hepatocyte replication and transformation, we isolated hepatocytes from mice bearing a human TGF-alpha transgene and examined their growth properties and gene expression in defined, serum-free culture. The transgenic hepatocytes continued to overexpress human TGF-alpha mRNA and peptide, and were able to proliferate without exogenous growth factors in primary culture, in contrast to nontransgenic mouse hepatocytes. In short-term culture the transgenic hepatocytes underwent 1 wave of DNA replication at 72-96 h in culture before senescing, similar to nontransgenic hepatocytes supplemented with epidermal growth factor. Constitutive expression of TGF-alpha rendered the transgenic hepatocytes unresponsive to further growth stimulation by exogenous TGF-alpha, as well as other mitogens such as epidermal growth factor and hepatocyte growth factor. However, it did not alter their sensitivity to growth inhibition by TGF beta 1, 2 and 3. The addition of nicotinamide to the culture medium enabled both transgenic and epidermal growth factor-supplemented normal hepatocytes to replicate repeatedly and survive for > or = 2 months in primary culture while maintaining differentiated traits. From these long-term primary cultures of transgenic and nontransgenic hepatocytes, we established immortalized cell lines (designated TAMH and NMH lines, respectively). Both lines continued to express differentiated adult hepatocytic markers such as albumin, alpha-1-antitrypsin, transferrin, and connexin 26 and 32 mRNAs, but also expressed mRNAs for the oncofetal markers alpha-fetoprotein and insulin-like growth factor II. Unlike the near-diploid NMH hepatocyte line, the transgenic TAMH hepatocyte line was quasi-tetraploid, strongly expressed human TGF-alpha mRNA, and was highly tumorigenic in nude mice. Well-differentiated hepatocellular carcinomas developed in nude mice given injections of the TAMH line, and these appeared similar to the primary liver tumors seen in TGF-alpha transgenic mice with regard to histology and strong expression of mouse and human TGF-alpha, insulin-like growth factor II, and alpha-fetoprotein mRNAs. Our data show that TGF-alpha overexpression causes autonomous hepatocyte proliferation and contributes to neoplasia but that additional cellular alterations must occur for carcinogenesis. Inappropriate expression of insulin-like growth factor II may constitute one of these steps. The TGF-alpha transgenic mouse hepatocyte line TAMH appears to undergo transformation in a similar manner to that of hepatocytes overexpressing TGF-alpha in vivo, and should serve as an ideal system in which to study hepatocarcinogenesis.
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PMID:Autonomous growth in serum-free medium and production of hepatocellular carcinomas by differentiated hepatocyte lines that overexpress transforming growth factor alpha 1. 752 51

Poly(ADP-ribose) is a homopolymer of ADP-ribose units synthesized from NAD+ on nuclear acceptor proteins and is known to be involved in DNA repair. It is not known whether large oral doses of the clinically utilized NAD precursors nicotinic acid or nicotinamide affect poly(ADP-ribose) metabolism or the cellular response to DNA damage. In our first study, using Fischer-344 rats, 2 wk of dietary nicotinic acid supplementation (500 and 1000 mg/kg diet) caused elevated levels of NAD+ in the blood, liver, heart and kidney, while nicotinamide caused elevated levels only in the blood and liver, compared with controls fed a diet containing 30 mg/kg nicotinic acid. Both nicotinic acid and nicotinamide, at 1000 mg/kg diet, caused elevations in liver NAD+, by 44 and 43%, respectively. Only nicotinamide, however, elevated liver poly(ADP-ribose) (63% higher than control group). Following treatment with the hepatocarcinogen diethylnitrosamine, higher levels of hepatic NAD+ were observed in rats fed both nicotinic acid and nicotinamide at 1000 mg/kg diet, but only nicotinic acid supplementation caused a greater accumulation of hepatic poly(ADP-ribose) (61% higher than control group). Neither of the dietary treatments significantly affected the proportion of the liver occupied by placental glutathione-S-transferase positive foci. These results show that poly(ADP-ribose) synthesis is not directly responsive to hepatic NAD+ levels during niacin supplementation, and that the mechanisms of action of nicotinic acid and nicotinamide are different. The observed changes in poly(ADP-ribose) metabolism do not appear to cause any change in susceptibility to chemically induced carcinogenesis in this organ.
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PMID:Large supplements of nicotinic acid and nicotinamide increase tissue NAD+ and poly(ADP-ribose) levels but do not affect diethylnitrosamine-induced altered hepatic foci in Fischer-344 rats. 778 98

Using rat liver microsomal preparations and peroxidase enzymes, we have investigated the formation of DNA adducts by the antiestrogen compound tamoxifen (TAM) and its metabolite 4-hydroxy-tamoxifen (4-OH-TAM). When reduced nicotinamide-adenine dinucleotide phosphate (NADPH) was used as a cofactor in microsomal activation of either 4-OH-TAM or TAM, one DNA adduct and relative DNA adduct levels of 4.6 and 3.1 x 10(-8), respectively were detected by 32P-postlabeling. The DNA adduct produced by microsomal activation of 4-OH-TAM and TAM was the same. With cumene hydroperoxide (CuOOH) as the cofactor for the microsomal activation of either 4-OH-TAM or TAM, three to six DNA adducts were produced; the relative adduct levels were 8.0 and 20.6 x 10(-8), respectively. Comparison of the DNA adduct patterns produced by 4-OH-TAM and TAM showed that they were distinct. However one of the DNA adducts (a) produced by microsomal activation of 4-OH-TAM using CuOOH was the same as adduct a produced by microsomal activation of 4-OH-TAM with NADPH. Activation of 4-OH-TAM with horseradish peroxidase resulted in the formation of a single DNA adduct and a relative adduct level of 20.7 x 10(-8). Rechromatography analysis of this DNA adduct showed that it was identical to that produced by microsomal activation of 4-OH-TAM with NADPH and one of the adducts produced using CuOOH as the cofactor. Ten DNA adducts and a relative adduct level of 15.3 x 10(-8) were detected in the liver of female Sprague-Dawley rats treated daily with 20 mg/kg of TAM for 7 days. The DNA adduct pattern in the liver of the treated animals was similar to that produced by microsomal activation of TAM using CuOOH as the co-factor. The principal DNA adduct (no. 6) formed in the livers of rats treated with TAM was the same as the principal DNA adduct formed following microsomal activation of TAM using CuOOH as a cofactor. The DNA adduct formed following microsomal activation of either TAM or 4-OH-TAM using NADPH was also present as one of the adducts (1) formed in vivo following TAM treatment. These studies demonstrate that 4-OH-TAM can be activated to form DNA adducts and that it contributes to the formation of DNA adducts in the liver of rats treated with TAM.
Carcinogenesis 1995 Jan
PMID:Microsomal and peroxidase activation of 4-hydroxy-tamoxifen to form DNA adducts: comparison with DNA adducts formed in Sprague-Dawley rats treated with tamoxifen. 783 94

Lidocaine (xylocaine) is utilized for the treatment of ventricular arrhythmias which occur during cardiac surgery or myocardial infarction and as a local anesthetic. Recent data from the National Toxicology Program reported that a principal metabolite in man, 2,6-dimethylaniline, is carcinogenic in rats. In addition, the putative metabolite N-hydroxy-2,6-dimethylaniline has been reported to be mutagenic in Salmonella typhimurium TA100. N-Hydroxy metabolites of aromatic amines may be oxidized by hemoglobin to the corresponding nitroso metabolites and the nitroso may covalently bind to cysteine groups in hemoglobin as the corresponding sulfinic acid amide. Since hemoglobin binding is an indirect measure of the formation of the N-hydroxy metabolite, we have examined the possibility that lidocaine or a metabolite may similarly covalently bind to hemoglobin in rats and humans. Using a previously developed gas chromatographic-mas spectrometric assay, hemoglobin adducts of 2,6-dimethylaniline were detected covalently bound to rat hemoglobin after administration of either 2,6-dimethylaniline or lidocaine. Consistent with previously reported observations, low levels of 2,6-dimethylaniline-hemoglobin adducts were also observed in human subjects before lidocaine administration. Following administration of lidocaine, all patients had much higher levels of 2,6-dimethylaniline-hemoglobin adducts. Differences in adduct levels in patients treated with lidocaine (70-3760 mg) ranged from 93 to 636 ng/g hemoglobin. These data indicate that N-hydroxy-2,6-dimethylaniline is a metabolite of lidocaine in man.
Carcinogenesis 1994 Oct
PMID:2,6-Dimethylaniline--hemoglobin adducts from lidocaine in humans. 795 68

Electron spin resonance (ESR) spectroscopy and oxygen consumption measurements using a Clark-type oxygen electrode have been used to study the metabolism of the estrogen 17 beta-estradiol by lactoperoxidase. Evidence for a one-electron oxidation of estradiol to its reactive phenoxyl radical intermediate is presented. The phenoxyl radical metabolite abstracts hydrogen from reduced glutathione generating the glutathione thiyl radical, which is spin trapped by 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and subsequently detected by ESR spectroscopy. In the absence of DMPO, molecular oxygen is consumed by a sequence of reactions initiated by the glutathione thiyl radical. Similarly, the estradiol phenoxyl radical abstracts hydrogen from reduced beta-nicotinamide-adenine dinucleotide (NADH) to generate the NAD. radical. The NAD. radical is not spin trapped by DMPO, but instead reduces molecular oxygen to the superoxide radical, which is then spin-trapped by DMPO. The superoxide generated may either spontaneously dismutate to form hydrogen peroxide or react with another NADH to form NAD., thus propagating a chain reaction leading to oxygen consumption and hydrogen peroxide accumulation. Ascorbate inhibits oxygen consumption when estradiol is metabolized in the presence of either glutathione or NADH by reducing radical intermediates back to their parent molecules and forming the relatively stable ascorbate radical. These results demonstrate that the futile metabolism of micromolar quantities of estradiol catalyzes the oxidation of much greater concentrations of biochemical reducing cofactors, such as glutathione and NADH, with hydrogen peroxide produced as a consequence. The accumulation of intracellular hydrogen peroxide could explain the hydroxyl radical-induced DNA base lesions recently reported for female breast cancer tissue.
Carcinogenesis 1994 Nov
PMID:The metabolism of 17 beta-estradiol by lactoperoxidase: a possible source of oxidative stress in breast cancer. 795 18

Using microsomal preparations from rat and human liver, we investigated the activation of the anti-estrogen compound tamoxifen (TMX) to form DNA adducts. Pretreatment of rats with phenobarbital increased DNA adduct formation by microsomal activation of TMX 3- to 6-fold, depending on the cofactors used. When reduced nicotinamide-adenine dinucleotide phosphate (NADPH) was used as a cofactor in human and rat microsomal activation systems, the relative DNA adduct levels were 2.9 and 5.2 x 10(-8) respectively and 1-3 TMX-DNA adducts were detected by 32P-postlabeling; DNA adduct 1 was the same in both microsomal systems. When cumene hydroperoxide (CuOOH) was used as a cofactor, activation of TMX produced four major DNA adducts and several minor DNA adducts in both rat and human liver microsomes; the relative adduct levels were 11.1 and 23.1 x 10(-8) respectively. TMX-DNA adducts 1, 4, 5 and 6 were similar in both human and rat microsomal systems with CuOOH as the cofactor. The TMX-DNA adducts formed with NADPH as the cofactor were clearly different from those formed with CuOOH as the cofactor, which implies that the metabolites leading to the individual DNA adducts were different. Addition of a P450 inhibitor, either n-octylamine or alpha-naphthylisothiocyanate, to the activation system reduced adduct formation by 70-93%. We propose that the TMX-DNA adducts formed with NADPH as the cofactor result from P450 acting as a mono-oxygenase, whereas the adducts formed with CuOOH as the cofactor result from P450 acting as a peroxidase. Our findings suggest that further studies may be required to establish the safety of TMX treatment of women for purposes other than chemotherapy.
Carcinogenesis 1994 Mar
PMID:DNA adduct formation by tamoxifen with rat and human liver microsomal activation systems. 811 38

Our understanding of the role of ADP-ribose polymer metabolism in limiting carcinogenic events and the dependence of this metabolism on cellular NAD levels predicts that niacin deficiency leading to reduced NAD levels may enhance carcinogenesis. This prediction has led us to initiate studies to evaluate the potential of niacin as a preventive factor in human cancer. The first approach involves development of a method to assess biochemically niacin status in humans using intracellular NAD derived from whole blood, primarily erythrocytes, as the relevant marker of niacin status. We have shown that erythrocyte NAD content varies by as much as 12-fold within a population and can be modulated readily by supplementation. A second approach to testing this hypothesis involves understanding the relationship of dietary niacin, circulating levels of NAD precursors (nicotinamide and nicotinic acid) and NAD in target tissues for human cancer. Current analytical methods for quantification of plasma levels of nicotinic acid and nicotinamide following intake in the dietary range are not sufficient. Thus, we have developed a GC-MS method for the rapid, sensitive, and selective determination of both nicotinamide and nicotinic acid in plasma. These methods will now allow assessment of niacin metabolism in humans that could lead to a new understanding of niacin in prevention of cancer.
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PMID:Evaluating the role of niacin in human carcinogenesis. 852 95

Using rat liver microsomal preparations, we have investigated the activation of the anti-estrogen compound tamoxifen (TAM) and its metabolite 4-hydroxytamoxifen (4-OH-TAM) to form 8-hydroxy-2'-deoxyguanosine (8-OH-dG) in DNA. When reduced nicotinamide adenine dinucleotide phosphate (NADPH) was used as a cofactor in microsomal activation of either TAM or 4-OH-TAM, the levels of 8-OH-dG were 3-fold higher than in microsomes plus cofactor only. In contrast, no significant increase in the level of 8-OH-dG was detected in DNA samples from microsomal activation of either TAM or 4-OH-TAM with cumene hydroperoxide as the cofactor. These results demonstrate that the microsomal activation of TAM and 4-OH-TAM to form 8-OH-dG is dependent upon the cofactor used. The addition of either EDTA or catalase to the activation system significantly decreased the formation of 8-OH-dG by TAM, but not by 4-OH-TAM. The presence of either sodium azide, superoxide dismutase or mannitol inhibited the formation of 8-OH-dG by both TAM and 4-OH-TAM. Taken together these findings indicate that microsomal activation of TAM and 4-OH-TAM with NADPH generates reactive oxygen species which result in the formation of 8-OH-dG. We propose that the formation of 8-OH-dG by TAM and its metabolites may contribute to the observed carcinogenic effects of TAM.
Carcinogenesis 1996 Aug
PMID:Production of 8-hydroxy-2'-deoxguanosine in DNA by microsomal activation of tamoxifen and 4-hydroxytamoxifen. 876 36

Weanling male F344 rats were fed either a semi-purified diet low in methionine and lacking in choline and folic acid (folate/methyl deficient) or a supplemented control diet for periods of 2, 5, 7 days, 3 weeks, and 9 weeks. Two days after initiating the folate/methyl deficient diet in weanling F344 rats, the incidence of apoptotic bodies, identified by in situ end-labeling of 3'-OH DNA strand breaks, was significantly increased in liver sections from the deficient rats. Apoptotic cell death was confirmed biochemically by an increase in nuclear Ca2+/Mg2+-dependent endonuclease activity that paralleled the increase in apoptotic bodies over the 9-week feeding period. There was no morphologic evidence of necrotic foci or necrosis-associated inflammatory response over the 9-week period. Confirming that cell turnover is chronically elevated in this model, the increase in apoptotic rate was accompanied by a sustained increase in the mitotic index (MI). The DNA repair-associated enzyme, poly(ADPribose) polymerase (PARP), was similarly elevated and was associated with significant decreases in the substrate for ADPribose polymer synthesis, nicotinamide adenine dinucleotide (NAD). Because folate metabolites are essential for de novo purine and thymidine biosynthesis, prolonged deficiency in folic acid can induce an imbalance in the deoxynucleotide precursors for DNA replication/repair and negatively affect the fidelity of DNA synthesis. Using an HPLC method, hepatic deoxyuridine triphosphate (dUTP) levels were increased at 3 and 9 weeks after initiation of the deficient diet and levels of thymidine triphosphate (dTTP) were reduced. An increase in dUTP/ dTTP ratio is consistent with a block in folate-dependent de novo thymidylate biosynthesis and may predispose to uracil misincorporation and DNA repair-related DNA strand breaks.
Carcinogenesis 1997 Feb
PMID:Apoptosis and proliferation under conditions of deoxynucleotide pool imbalance in liver of folate/methyl deficient rats. 905 20


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