Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: B0001 .4
 471,332 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thymidine was permitted to react with the known mutagens acrolein and 2-bromoacrolein under physiological conditions. The products of these reactions were separated by HPLC and characterized by UV, FAB/MS, electrospray MS, 1H NMR and chemical transformation. The reaction with acrolein gave one major product, N3-(3''-oxopropyl)thymidine, which is unstable in aqueous solution and was reduced with sodium borohydride to the corresponding alcohol. Reaction with 2-bromoacrolein yielded the unstable intermediate, N3-(2''-bromo-3''-oxopropyl)thymidine, and two stable products, the diastereomers of N3-(2''-hydroxy-3''-oxopropyl)thymidine, which are slowly transformed to N3-(2''-oxo-3''-hydroxypropyl)thymidine. Reactions with both mutagens proceed most rapidly at pH 9.2, less rapidly at pH 7.4, and no products are found at pH 4.2. Stable adducts found in the reaction of 2-bromoacrolein were also identified in reactions with single-strand oligodeoxynucleotides using a sensitive, selected ion monitoring GC/MS procedure.
Carcinogenesis 1992 Dec
PMID:Characterization of thymidine adducts formed by acrolein and 2-bromoacrolein. 147 45

A time- and dose-dependent study of N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN) bladder carcinogenesis was performed in nude mice maintained on tap water containing 0.025% EHBN for 4, 12, and 20 weeks ad libitum. A total of 13 invasive tumors, comprising 11 transitional cell carcinomas (TCCs) (84.6%) and 2 squamous cell carcinomas (SCCs) (15.4%), were found. Compared with previous results for B6C3F1 mice exposed to the same EHBN insult, the numbers of invasive carcinomas induced in nude mice, and especially of SCCs, were low. In order to ascertain whether this difference in cancer incidence between nude and B6C3F1 mice was due to variation in urinary excretion, the metabolism of EHBN was also investigated and compared with that of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Respective total urinary excretions over 48 hr of N-ethyl-N-(3-carboxypropyl)nitrosamine (ECPN) or N-butyl-N-(3-carboxypropyl)nitrosamine (BCPN), the ultimate carcinogenic species of EHBN or BBN, were 822.4 +/- 41.4 micrograms and 530.4 +/- 81.0 micrograms, respectively, in nude mice, and 800.6 +/- 83.7 micrograms and 407.8 +/- 69.7 micrograms, respectively, in B6C3F1 mice. In conclusion, although it is apparent that nude mice have a low susceptibility to EHBN induction of urinary bladder cancer, this does not appear to be dependent on reduced metabolism to the active form.
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PMID:Low susceptibility of nude mice to induction of invasive urinary bladder cancers by N-ethyl-N-(4-hydroxybutyl)nitrosamine. 147 81

Estrogen receptor (ER) levels were evaluated in thyroid tumors induced by N-methyl-N-nitrosourea (MNU) and low iodine diet (LID) or propylthiouracil (PTU) in intact and estrogen (E2) loaded Long-Evans (LE) rats. MNU at 40 mg/kg body wt was injected in 50 day-old LE rats of both sexes. The animals were killed 17-22 weeks later and the thyroid tissues were subjected to ER assay. In LID-treated groups, cytosolic ER (cER) levels were 6.7 +/- 5.8 (fmol/mg protein, mean +/- SE) in females and 0.7 +/- 1.4 in males, E2 increased the ER levels. In E2-loaded LID groups, cER levels were 12.9 +/- 3.7 in females and 1.7 +/- 1.7 in males. PTU treatment produced almost comparable ER levels as LID treatment. PTU treatment as well as LID treatment increased the serum TSH levels with E2 treatment producing additional elevation. In evaluating ER levels by histological type of thyroid tumors, the level in cER plus nER showed the lowest value of 6 +/- 6.4 (fmol/mg DNA, mean +/- SE) in hyperplasia, followed by 129 +/- 52.3 in adenoma and 289 +/- 51.7 in carcinoma. The rates of BrdU incorporation in thyroid follicles indicated higher proliferation activity in the area of adenoma and carcinoma rather than in the hyperplastic area. These data suggested that E2 treatment increases the ER levels in MNU and LID/PTU-induced thyroid tumors. The level of ER was correlated to the histological type of thyroid tumors.
Carcinogenesis 1992 Aug
PMID:Increase in estrogen receptor levels in MNU-induced thyroid tumors in LE rats. 149 82

The rat lung and nasal cavity are two target organs for carcinogenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In order to characterize further the enzymes involved in the bioactivation of NNK, detailed kinetic and inhibitory studies were conducted with rat lung and nasal mucosa microsomes, and the results were compared with previous studies. The enzymes in rat lung microsomes catalyzed the alpha-hydroxylation, pyridine N-oxidation and carbonyl reduction of NNK. The apparent Km for the formation of the NNK-derived keto aldehyde, NNK-N-oxide, the NNK-derived keto alcohol and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol were 28.8, 10.4, 7.0 and 178.1 microM respectively. In rat nasal microsomes, alpha-hydroxylation was the predominant pathway and the rate was approximately 200 times higher than that in lung microsomes. The apparent Kms for keto aldehyde and keto alcohol formation in rat nasal microsomes were 9.6 and 10.1 microM respectively. The cytochrome P450 inhibitors metyrapone and carbon monoxide markedly inhibited the metabolism of NNK in both rat lung and nasal microsomes. In rat lung microsomes, alpha-naphthoflavone and monospecific antibodies against P450s 1A2, 2A1 and 2B1 inhibited the formation of keto aldehyde by 39, 46, 64 and 23% respectively. In rat nasal microsomes, alpha-naphthoflavone and antibodies against P450s 1A2, 2A1 and 3A inhibited the metabolism of NNK by 80, 35, 20 and 14% respectively. The results indicate that cytochromes P450 play a major role in the metabolic activation of NNK in rat lung and nasal microsomes, and that there are tissue-related differences in NNK metabolism.
Carcinogenesis 1992 Aug
PMID:Kinetics and enzyme involvement in the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in microsomes of rat lung and nasal mucosa. 149 91

Three different activated supports were used to immobilize alpha-O6-methyldeoxyguanosine (O6-MedG) monoclonal antibody. Affinity gels based on CNBr Sepharose, Affigel Hz and periodate-activated Sepharose (PIAS) were able to bind 1.4, 1.5 and 6.2 nmol [3H]O6-MedG/mg immobilized IgG respectively, and recovery of bound material exceeded 95% in all cases. Significant non-specific binding of normal nucleosides occurred only when using the CNBr gel. PIAS alpha-O6-MedG affinity gel was able to purify O6-MedG-3'-monophosphate from digested synthetic oligonucleotides and in vitro-methylated calf thymus DNA to allow subsequent detection by 32P-postlabelling and two-dimensional TLC. The combined method was applied to three human samples and O6-MedG levels of 0.39, 0.38 and 0.45 mumol/mol 2'-deoxyguanosine were found. The minimum detection limit of the combined method is expected to be approximately 1 O6-MedG in 10(8) normal 2'-deoxyguanosines (i.e. approximately 30 lesions per human cell) when 100 micrograms of DNA is used.
Carcinogenesis 1992 Mar
PMID:Immunoaffinity purification combined with 32P-postlabelling for the detection of O6-methylguanine in DNA from human tissues. 154 39

To evaluate risk factors for cervical intraepithelial neoplasia (CIN), data were collected in a case-control study based on 366 patients (58 with CIN class 1, 70 with CIN class 2, and 238 with CIN class 3) and 323 control subjects with normal cervical smears interviewed on selected days at the same screening clinics where cases had been identified. No relationship emerged between indicators of socioeconomic status (education and social class) and risk of mild/moderate (considered together) and severe dysplasia. A total of 55 (43%) patients with CIN class 1 or 2, 107 (45%) patients with CIN class 3, and 94 (29%) controls were current smokers. The corresponding relative risk (RR) estimates for current versus never smokers were 1.9 (95% confidence interval [CI] 1.2 to 3.0) for patients with CIN class 1 or 2 and 2.5 (95% CI 1.7 to 3.6) for patients with CIN class 3, and the risk increased with the number of cigarettes smoked per day. No relationship was observed between oral contraceptive use, parity, spontaneous or induced abortions and the risk of CIN, but patients tended to report earlier age at first birth than control subjects. Compared with women reporting their first birth before the age of 20 years, the risk estimates were 0.5 and 0.4, respectively, for patients with CIN 1 or 2 and patients with CIN 3 in women reporting first birth at 20 to 24 years of age. The risk estimates were 0.5 and 0.6 for those reporting their first birth at age 25 or later, but the trends in risk were not statistically significant. The number of sexual partners was directly associated with the risk for both histopathologic subgroups. Compared with women reporting no intercourse or their first intercourse after 22 years of age, women with first intercourse before the age 18 had a RR estimate of CIN class 1 or 2 of 2.3 and of CIN class 3 of 2.4, with the trends in risk being statistically significant. This study confirms considerable similarities in the epidemiology of mild/moderate and severe cervical dysplasia. In addition, it suggests consistency between the epidemiology of intraepithelial and invasive cervical neoplasia for risk factors that are likely to act on one of the first stages of the process of carcinogenesis (i.e., indications of sexual habits) but differences for hormone-mediated factors (i.e., reproductive variables or oral contraceptives).
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PMID:Risk factors for cervical intraepithelial neoplasia. 156 73

In the present investigation, we have examined the role of lipoxygenases in the bioactivation of aflatoxin B1 (AFB1) in hepatic and extrahepatic tissues. The enzyme activities were evaluated by determining [3H]AFB1-DNA adduct formation. The results demonstrated that both purified soybean lipoxygenase and guinea-pig tissue cytosolic lipoxygenases were able to activate AFB1 to form [3H]AFB1-DNA adduct(s). The reaction was completely inhibited by nordihydroguaiaretic acid (NDGA, 0.1 mM), a lipoxygenase inhibitor and an antioxidant, but not by indomethacin (0.1 mM), an inhibitor of prostaglandin H synthase (PHS), indicating that this reaction is associated with lipoxygenase activity, and/or is involved in a peroxyl radical process. While purified lipoxygenase showed arachidonic acid (AA)-dependent properties, the omission of AA did not diminish guinea-pig tissue cytosolic [3H]AFB1-DNA adduct formation, possibly because AA was released from lipid particles by AFB1. Within the range of hemoglobin (Hb) concentrations found in lung, kidney and liver cytosols (1.4-11.1 microM) and microsomes (0-0.5 microM), neither pure Hb, nor Hb of cytosols or microsomes from whole blood caused detectable AA-dependent AFB1-DNA binding. This indicates that Hb, as a contaminant with quasi-lipoxygenase activity, did not contribute to AFB1 activation attributed to guinea-pig tissue lipoxygenases. [3H]AFB1 concentrations at half-maximal DNA binding rate of pulmonary cytochrome P450 monooxygenases (P450) and lipoxygenases were similar, though P450 had a much higher maximum DNA binding rate. Pulmonary microsomal PHS activity for AFB1 activation was too low for its half-maximal binding concentrations of [3H]AFB1 and maximum rate to be accurately determined. In kidney, maximum rates for lipoxygenase, PHS and P450 were similar, whereas half-maximal binding concentrations for reactions by lipoxygenase and P450 were lower compared to that of PHS. The half-maximal binding concentration of hepatic lipoxygenase was significantly lower than those for PHS and P450. Hepatic half-maximal binding concentrations for PHS and P450 were similar, though P450 had a much higher maximum rate than PHS and lipoxygenases. These data suggest that lipoxygenase-catalyzed AFB1 activation can occur at low AFB1 concentrations. This may be important in view of human exposure to low AFB1 concentrations and predominant lipoxygenase activity in human airway epithelial cells. When expressed per gram of tissue, renal and hepatic PHS activities and renal lipoxygenase activities for AFB1 activation were similar, and higher than the activity of pulmonary PHS, while pulmonary PHS activity for the oxidation of N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) was similar to that in liver and lower than that in kidney.(ABSTRACT TRUNCATED AT 400 WORDS)
Carcinogenesis 1992 Apr
PMID:Bioactivation of aflatoxin B1 by lipoxygenases, prostaglandin H synthase and cytochrome P450 monooxygenase in guinea-pig tissues. 157 4

It has been suggested that the endogenous nitrosation of aliphatic, cyclic and heterocyclic secondary amines in the urinary bladder of patients with chronic urinary bacterial infections and in the human stomach may provide an important additional source of exposure to carcinogenic volatile N-nitrosamines. The most commonly occurring nitrosatable secondary amines found in human saliva, gastric juice, blood, urine and faeces are dimethylamine (DMA), pyrrolidine (PYR) and piperidine (PIP). All of 40 analysed samples of gastric juice contained 0.87 +/- 0.89 (SEM) microgram/ml DMA, 39 contained 1.35 +/- 2.53 microgram/ml PIP, 36 contained 0.18 +/- 0.15 microgram/ml PYR and 14 contained 0.05 +/- 0.11 microgram/ml diethylamine. Nitrate (14.0 +/- 15.7 microgram/ml) was present in all samples and 11 of 40 samples contained 0.43 +/- 1.38 microgram/ml nitrite. Only one gastric juice sample with pH less than 4.5 contained nitrite (0.1 microgram/ml). In paraplegics, patients with bladder augmentations and two control groups without bacterial infections of the urinary bladder, a mean daily excretion of 40.5-49.7 mg/day DMA, 19.4-23.8 mg/day PYR and 26.1-31.7 mg/day PIP was found. In both patient groups suffering from chronic bacterial infection of the urinary bladder, the corresponding volatile N-nitrosamines were formed by endogenous nitrosation and excreted in urine.
Carcinogenesis 1992 Apr
PMID:Secondary amine precursors to nitrosamines in human saliva, gastric juice, blood, urine and faeces. 157 7

Cellular oncogenes such as c-fos, c-jun and c-myc are expressed prior to estrogen-induced growth of normal target tissues such as rodent uterus. Transient increases in the levels of these genes are induced by the administration of estradiol and are followed by DNA replication. In this study, we examined the expression of these three oncogenes in estradiol-induced kidney tumors in Syrian hamsters in order to understand mechanistic aspects of hormonal carcinogenesis. Kidney tumors were induced in all male Syrian hamsters treated chronically with estradiol for 7 or 9 months, whereas neoplasms were not detected in animals treated for 5 months. mRNA levels of fos, myc and jun were elevated 15-, 4- and 6-fold respectively in kidney tumors of estradiol-treated hamsters (9 months) compared with age-matched untreated control kidneys. The expression of all three protooncogenes was also increased in the kidney tissue surrounding tumors, though there was no consistent pattern in the ratios of transcripts in the tumor and kidney tissues. After 7 months of estrogen treatment, kidney tumors also contained elevated amounts of c-fos, c-jun and c-myc transcripts at levels comparable with older tumors. In abdominal metastases of hamster kidney tumors, mRNA levels of fos, myc and jun were elevated 9-, 12- and 3-fold respectively over control levels. In kidneys of hamsters treated with estradiol for 5 months, in which tumors were not yet detected, the expression of protooncogenes was slightly increased. Ratios of c-fos, c-myc and c-jun in estrogen-treated (5 months) over control tissue were 1.4, 1.1 and 1.3 respectively. Overexpression of cellular oncogenes such as c-fos, c-jun and c-myc may have played a role in the induction and growth of kidney tumors by estradiol in hamsters.
Carcinogenesis 1992 Apr
PMID:Elevation of protooncogene messenger RNAs in estrogen-induced kidney tumors in the hamster. 157 13

We examined protein kinase C (PKC) activity in the cytosolic and particulate fractions of homogenates obtained from 25 colorectal adenomas and adjacent normal mucosa in patients with colorectal carcinoma. The total PKC activity of colorectal adenomas was significantly reduced compared with that of normal mucosa in all cases (122 +/- 45.8 vs 174 +/- 50.5 pmol min-1 mg-1) (means +/- s.d.) (P less than 0.001). The particulate fraction PKC activity of adenomas was also significantly lower than in normal mucosa (71.4 +/- 31.3 vs 115 +/- 39.6 pmol min-1 mg-1) (P less than 0.001). Adenomas were classified by size, histological type and degree of dysplasia. The average particulate PKC activity ratio (adenoma/normal mucosa) of tubulovillous adenomas or those with severe dysplasia was significantly reduced compared with that of tubular adenomas or tumours with mild and moderate dysplasia (both P less than 0.001), while there were no significant differences in the cytosolic PKC activity ratio. The particulate PKC activity ratio decreased significantly with increasing adenoma size (P less than 0.001), while the cytosolic ratio again showed no difference. These findings suggested that the particulate PKC activity ratio had a possible correlation with the malignant potential of colorectal adenomas and that this ratio may be a useful biological indicator of colorectal carcinogenesis.
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PMID:Correlation between protein kinase C activity and histopathological criteria in human colorectal adenoma. 158 95


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