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)

Mitotic gene conversions, among other recombinagenic events, can play an important role in the multistep process of carcinogenesis. The ability of chemicals to induce such gene conversions can easily be monitored in the Saccharomyces cerevisiae tester strain YHE2, a derivative of strain D7. For the detection of drug-induced gene conversions, two mutations in the TRP5 locus are used, trp5-12 and trp5-27. Here we report on the characterization of the stable allele trp5-27. Our analysis revealed two relevant mutations in trp5-27: (a) a transition C to T at position 121 after ATG that results in an amber stop codon and abolishes gene expression and (b) a transversion A to T at position 1555 that creates an ochre stop codon. Simultaneous amber and ochre suppression with the suppressors SUP3 and SUP11, respectively, was capable of relieving the tryptophan-requiring phenotype of strains carrying the trp5-27 allele. These findings have implications on the length of gene conversion tracts in conversion events between trp5-12 and trp5-27: conversion tracts can cover several kilobases, if the site of the mutation in trp5-12 lies outside of the positions mutated in trp5-27. Conversely, the maximal length is limited to 1435 bp, if the mutation in trp5-12 is located between the positions mutated in trp5-27.
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PMID:Characterization of the trp5-27 allele used to monitor drug-induced mitotic gene conversion in the Saccharomyces cerevisiae tester strain D7. 796 81

The flavonoid, quercetin, is known to bind to DNA and, in the presence of Cu(II) and other ions, causes fragmentation of the molecule. We examined whether quercetin might bind to protein and cause similar fragmentation. By using UV spectroscopic and fluorescence quenching experiments we show that quercetin binds to bovine serum albumin and that the complex does, in the presence of Cu(II), lead to fragmentation of the protein. The binding involves binding to tryptophan residues in the albumin. The reaction is not detected in certain other tryptophan-containing proteins. We discuss the possible implications for protein damage by this and other radical-generating reagents.
Carcinogenesis 1994 Aug
PMID:Free radical-induced fragmentation of proteins by quercetin. 805 42

Poly(ADP-ribose) is synthesized on nuclear proteins in response to DNA damage and plays an important role in DNA repair. Niacin and tryptophan are dietary precursors to NAD+, which is the substrate for poly(ADP-ribose) synthesis. This study examined the influence of niacin status on poly(ADP-ribose) metabolism and carcinogenesis. Diets devoid of added niacin, with different levels of tryptophan, were used to produce moderate and severe niacin deficiencies in male Fischer-344 rats. Control rats were pair fed niacin-replete diets. After a 21-day feeding period, rats were injected with diethylnitrosamine (DEN) (Expt 1, 200 mg/kg ip; Expt 2, 100 mg/kg ip). In Experiment 1, blood and liver NAD+ and liver poly(ADP-ribose) were measured over the next 15 hours. Whereas blood and liver NAD+ were decreased by niacin deficiency, blood NAD+ was not affected by DEN. Liver NAD+ decreased significantly in response to DEN treatment in the pair-fed groups, but it did not change in the niacin-deficient groups. Unexpectedly, at 10 hours postinjection, liver poly(ADP-ribose) accumulation was greater (p < 0.05) in the niacin-deficient than in the pair-fed rats (n = 9), despite lower initial NAD+ levels and a lack of NAD+ disappearance in niacin-deficient livers. In Experiment 2, livers were examined for the presence of altered hepatic foci three months after DEN exposure. There were no significant differences in the percentage of liver occupied by foci between the niacin-deficient and pair-fed groups (n = 8). These results indicate that niacin-deficient rats were able to accumulate higher concentrations of hepatic poly(ADP-ribose) in response to DEN and did not show elevated susceptibility to initiation of altered hepatic foci.
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PMID:The effect of niacin deficiency on diethylnitrosamine-induced hepatic poly(ADP-ribose) levels and altered hepatic foci in the Fischer-344 rat. 858 47

Rat liver 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase (3 alpha-HSD) inactivates circulating steroid hormones and is involved in polycyclic aromatic hydrocarbon (PAH) carcinogenesis. It is the only HSD of known structure in the aldo-keto reductase (AKR) superfamily and may provide a paradigm for other mammalian HSDs in this family. The structure of the 3 alpha-HSD.NADP+ binary complex has been determined at 2.7 A resolution and refined to a crystallographic R-factor of 23.4% with good geometry. The model is similar to other binary complexes in the AKR superfamily in that NADP+ binds at the C-terminal end of an alpha/beta barrel. However, it is unique in that NADP+ is bound in two alternate conformations, probably because of the lack of a salt-linked "safety belt" over the pyrophosphate bridge. The structure supports a previously proposed catalytic mechanism for carbonyl reduction in which Tyr 55 is the general acid, and its effective pKa is lowered by the adjacent Lys 84. We present evidence that the structurally distinct short-chain dehydrogenase/reductase (SDR) superfamily may have convergently evolved a similar catalytic mechanism. Insight into substrate binding is offered by a crystal packing contact in which a neighboring molecule inserts a tryptophan residue (Trp 227) into an apolar cleft in 3 alpha-HSD. This cleft is proximal to the bound NADP+ cofactor and contains a surface of apolar residues (Leu 54, Trp 86, Leu 122, Phe 128, Phe 129, Leu 137, Phe 139), making it a likely candidate for the substrate-binding site. Thus, in forming this crystal contact, Trp 227 may mimic a portion of a bound steroid. In addition, we propose that a water molecule in the active site indicates the position of the hydroxyl oxygen in a 3 alpha-hydroxysteroid substrate. Knowledge of the position of this water molecule, combined with the stereochemistry of hydride transfer, suggests that the alpha face of a bound steroid will be oriented toward the side of the apolar cleft containing Trp 86.
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PMID:Structure of 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase complexed with NADP+. 871 59

Inactivation of O6-alkylguanine-DNA alkyltransferase by O6-benzylguanine renders tumor cells more sensitive to killing by methylating and chloroethylating agents, and O6-benzylguanine is currently undergoing clinical trials for development as an agent to enhance chemotherapy. It has been reported recently that a polymorphism in the human O6-alkylguanine-DNA alkyltransferase gene exists, with about 15% of the population studied having arginine at codon 160 instead of glycine (Y. Imai et al., Carcinogenesis (Lond.), 16: 2441-2445, 1995). We have studied the effects of mutations of this glycine to arginine, tryptophan, or alanine on the interaction of human alkyltransferase with O6-benzylguanine using direct determination of the amount of activity remaining after incubation with various concentrations of the inhibitor and measurement of the rate of production of [8-3H]guanine from O6-benzyl[8-3H]guanine as assays. These mutations had little effect on the alkyltransferase activity in repairing O6-methylguanine in methylated DNA. Alteration of glycine 160 to tryptophan or alanine slightly increased the sensitivity to O6-benzylguanine (by up to 4-fold). However, alteration of glycine 160 to arginine drastically reduced the inactivation by O6-benzylguanine with at least a 20-fold increase in the ED50 value and a similar reduction in the production of guanine whether inactivation was carried out in the absence or presence of DNA. These results raise the possibility that a subpopulation of patients may be resistant to O6-benzylguanine and that higher doses or additional alkyltransferase inhibitors capable of inactivating this form of the alkyltransferase will be necessary.
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PMID:Resistance of the human O6-alkylguanine-DNA alkyltransferase containing arginine at codon 160 to inactivation by O6-benzylguanine. 897 Nov 55

This review covers the historical developments of the consideration that tryptophan may influence the induction of cancer in experimental studies. Studies relating to stimulatory effects, as well as to inhibitory effects, of tryptophan or tryptophan-related compounds are described. Also the effects of pyrolysis products of tryptophan on carcinogenesis are covered. In consideration that new L-tryptophan-related contaminants may be involved in a recently described human disease, a description is given of the eosinophilia-myalgia syndrome, which has been attributed to the ingestion of L-tryptophan-containing related contaminants. Whether these new L-tryptophan-related contaminants alone or together with L-tryptophan may prove to be carcinogenic remains to be determined. Lastly, recent developments relating to regulatory effects of L-tryptophan on liver metabolism are reviewed and then considered as possibly playing a role in carcinogenesis.
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PMID:Tryptophan and carcinogenesis: review and update on how tryptophan may act. 968 53

Previous studies have identified allelic variants of the human glutathione transferase (GST) Pi gene and showed that the two different encoded proteins with isoleucine (GSTP1-1/I-105) or valine (GSTP1-1/V-105) at position 105, respectively, differ significantly in their catalytic activities with model substrates. Moreover, recent epidemiological studies have demonstrated that individuals differing in the expression of these allelic variants also differ in susceptibility to tumour formation in certain organs, including such in which polycyclic aromatic hydrocarbons (PAH) may be etiological factors. In the present study the catalytic efficiencies (kcat/Km) of these GSTP1-1 variants were determined with a number of stereoisomeric bay-region diol epoxides, known as the ultimate mutagenic and carcinogenic metabolites of PAH, including those from chrysene, benzo[a]pyrene and dibenz[a,h]anthracene. In addition, GSTP1-1 mutants in which amino residue 105 is alanine (GSTP1-1/A-105) or tryptophan (GSTP1-1/W-105) have been constructed and characterized. GSTP1-1/V-105 was found to be more active than GSTP1-1/I-105 in conjugation reactions with the bulky diol epoxides of PAH, being up to 3-fold as active towards the anti- and syn-diol epoxide enantiomers with R-absolute configuration at the benzylic oxiranyl carbon. Comparing the four enzyme variants, GSTP1-1/A-105 generally demonstrated the highest kcat/Km value and GSTP1-1/W-105 the lowest with the anti-diol epoxides. A close correlation was observed between the volume occupied by the amino acid residue at position 105 and the value of kcat/Km. With the syn-diol epoxides, such a correlation was observed with alanine, valine and isoleucine, whereas tryptophan was associated with increased kcat/Km values. The mutational replacement of isoleucine with alanine or tryptophan at position 105 did not alter the enantio selectivity of the GSTP1-1 variants compared with the naturally occurring allelic variants GSTP1-1/I-105 and GSTP1-1/V-105. Since the amino acid at position 105 forms part of the substrate binding site (H-site) the effect of increasing bulkiness is expected to cause restricted access of the diol epoxide and proper alignment of the two reactants for efficient glutathionylation. In conclusion, the present study indicates that individuals who are homozygous for the allele GSTP1* B (coding for GSTP1-1/V-105) display a higher susceptibility to malignancy because of other factors than a decreased catalytic efficiency of GSTP1-1/V-105 in the detoxication of carcinogenic diol epoxides of benzo[a]pyrene or structurally related PAH.
Carcinogenesis 1998 Mar
PMID:Differences in the catalytic efficiencies of allelic variants of glutathione transferase P1-1 towards carcinogenic diol epoxides of polycyclic aromatic hydrocarbons. 952 77

Most available data on the involvement of p53 in rodent carcinogenesis are based on results of the end point of chemically or virally induced carcinogenesis, i.e., tumors. To investigate the role of altered p53 expression in early stages of rodent hepatocarcinogenesis in a systematic way, we treated male Wistar rats for 6 wk, for 13 wk, and for 6 wk followed by a 7-wk recovery period with chemicals classified as genotoxic (200 ppm acetylaminofluorene [AAF], 100 ppm N-nitrosomorpholine [MMN], 200 ppm benzo(a)pyrene), as tumor promoters and carcinogenic in experimental animals (5 ppm ethinylestradiol, 500 ppm phenobarbitone, 3,000 ppm clofibric acid), as carcinogenic in animal experiments (600 ppm thioacetamide), as noncarcinogenic (200 ppm thyroxine), and as tumor promoters in experimental animals (20,000 ppm tryptophan, 120,000 ppm fructose). Immunohistochemical assessment of altered p53 expression on liver sections with polyclonal serum (CM5) resulted in positive staining in 17/21 benzo(a)pyrene-, 1/18 thioacetamide-, 2/21 clofibric acid-, 2/21 phenobarbitone-, 7/19 ethinylestradiol-, 1/21 tryptophan-, 3/19 thyroxine-, and 1/21 fructose-treated rats and in 2/19 controls. These data support earlier results obtained from analogous investigations with a high incidence of altered p53 expression after NNM and AAF treatment. Thus, altered p53 expression appears to be an early and frequent event in rodent carcinogenesis induced by genotoxic chemicals in contrast to most epigenetically acting chemicals.
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PMID:Altered p53 expression in early stages of chemically induced rodent hepatocarcinogenesis. 978 50

Basal-cell carcinomas (BCCs) are the most common cancer in Caucasians. It has been reported that the patched gene is inactivated in 30-40% sporadic BCCs and 20% sporadic medulloblastomas via loss of heterozygosity and nonsense mutations. Recently, two activating smoothened mutations have been found in the sporadic basal cell carcinomas. One, at base pair 1604 (G-to-T transversion) of exon 9, changes codon 535 from tryptophan to leucine, and the other, at base pair 1685 (G-to-A transition) of exon 10, changes codon 562 from arginine to glutamine (Xie et al., 1998). In our study, 1604G-->T was found in 20 out of 97 (20.6%) sporadic BCCs. The high prevalence indicates that 1604G is the mutation hot spot in our tumor samples. This mutation was detected in all three histological subtypes of BCCs, suggesting that smoothened mutation is an early event during the development of the tumor. Our finding of a high smoothened mutation rate, together with high frequent patched gene mutations reported recently, indicates that activation of the hedgehog signal transduction pathway is the most common and early event in the development of sporadic BCCs. Additionally, to determine whether smoothened, like patched, is also involved in the carcinogenesis of medulloblastomas, we screened medulloblastoma samples for these two mutations by restriction analysis. We have found the 1604G-->T mutation in 1 out of 21 medulloblastomas. This result confirmed smoothened gene involvement in the carcinogenesis of medulloblastoma.
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PMID:A frequent activated smoothened mutation in sporadic basal cell carcinomas. 998 36

Excessive free iron and the associated oxidative damage are commonly related to carcinogenesis. Among the antioxidants known to protect against iron-induced oxidative abuse and carcinogenesis, melatonin and other indole compounds recently have received considerable attention. Indole-3-propionic acid (IPA), a deamination product of tryptophan, with a structure similar to that of melatonin, is present in biological fluids and is an effective free radical scavenger. The aim of the study was to examine the effect of IPA on experimentally induced oxidative changes in rat hepatic microsomal membranes. Microsomes were preincubated in presence of IPA (10, 3, 2, 1, 0.3, 0.1, 0.01 or 0.001 mM) and, then, incubated with FeCl(3) (0.2 mM), ADP (1.7 mM) and NADPH (0.2 mM) to induce oxidative damage. Alterations in membrane fluidity (the inverse of membrane rigidity) were estimated by fluorescence spectroscopy and lipid peroxidation by measuring concentrations of malondialdehyde+4-hydroxyalkenals (MDA+4-HDA). IPA, when used in concentrations of 10, 3 or 2 mM, increased membrane fluidity, although at these concentrations it did not influence lipid peroxidation significantly. The decrease in membrane fluidity due to Fe(3+) was completely prevented by preincubation in the presence of IPA at concentrations of 10, 3, 2 or 1 mM. The enhanced lipid peroxidation due to Fe(3+) was prevented by IPA only at the highest concentration (10 mM). It is concluded that Fe(3+)-induced rigidity and, to a lesser extent, lipid peroxidation in microsomal membranes may be reduced by IPA. However, IPA in high concentrations increase membrane fluidity. Besides melatonin, IPA may be used as a pharmacological agent to protect against iron-induced oxidative damage to membranes and, potentially, against carcinogenesis.
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PMID:Indole-3-propionic acid, a melatonin-related molecule, protects hepatic microsomal membranes from iron-induced oxidative damage: relevance to cancer reduction. 1125 33


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