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H Autrup

Publications and source records attributed to H Autrup.

At least 55 records · Page 3Linked to original sources
PubMed1990

Deregulation in trans or c-myc expression in immortalized human urothelial cells and in T24 bladder carcinoma cells.

The expression of a number of cellular oncogenes was investigated in human urothelial cell lines with different in vitro growth properties. Constitutively elevated levels of expression of c-myc RNA were found in Hu609, an immortalized, nontumorigenic cell line that was derived from normal urothelium, and in the bladder carcinoma cell line T24. Potential mechanisms that might underlie deregulation of c-myc expression in these cells were investigated. It was found that the c-myc gene was apparently intact and not amplified in Hu609 and T24. No increased stability of c-myc RNA was detected. A c-myc-CAT fusion construct containing 2.5 kb of normal c-myc 5' sequences showed levels of expression that paralleled the overexpression of the endogenous gene, indicating that the high constitutive levels of c-myc expression were due, at least in part, to alterations in the activities of cellular trans-acting transcriptional regulators.

Animals↗
PubMed1990

Extracts of airborne particulates collected at different locations in the Copenhagen area induce the expression of cytochrome P-450IA1.

Acetone extracts of airborne particulates collected at different sites in the greater Copenhagen area were tested for their ability to induce the expression of cytochrome P-450IA1 RNA in a human breast cancer cell line, T47-D. The induction efficiency was expressed as an benz[a] anthracene equivalents, that is, the amount of benz[a]anthracene required to give the same level of induction. A significantly higher level of induction of P-450IA1 RNA was seen with samples collected on days with a smog alert. The inducibility of samples collected in rural areas was lower, but no significant difference in inducibility was found between samples collected in urban and suburban areas. Lack of correlation between the mutagenic activity in the Ames assay and the P-450IA1-inducing activity of the samples suggests that the complex mixture of compounds found in airborne particulates may have different biological activities in the two short-term test systems. Measurements of P-450IA1 inducibility provide a new, sensitive approach to assess the biological activity of material present in air pollution. The presence in airborne particulates of chemical compounds that induce cytochrome P-450IA1 an enzyme responsible for the metabolism of ubiquitous chemical carcinogens, suggests that the general environment may change an individual's response to the impact of exogenous chemicals, including the carcinogens present in cigarette smoke.

Air Pollutants↗
PubMed1990

Carcinogen metabolism in cultured human tissues and cells.

A large number of chemical carcinogens require metabolic activation before they are biologically active. The metabolism of a few of these compounds has been investigated in cultured human tissues and cells and the metabolism has been compared with the metabolism in organs from experimental animals in which the compounds induce cancer. Generally, only quantitative differences could be observed between animal and human tissues. The development of new methods to detect carcinogen-DNA adducts makes it feasible to study and compare the metabolism in human and animal tissues of an increasing number of potential human carcinogens. Furthermore, construction of cell lines, expressing the human forms of the carcinogen metabolizing enzymes, by biotechnology provides a new model to study the metabolism and to monitor for genetic markers in the same cells.

Animals↗
PubMed1990

Induction of cytochrome P450IA1 in rat colon and liver by indole-3-carbinol and 5,6-benzoflavone.

It is known that consumption of cruciferous vegetables protects against the chemical induction of cancer in many organs. It has been suggested that this protection is mediated through an effect on the cytochrome P450 monooxygenase system. This system is responsible for the activation of a number of chemical carcinogens to their ultimate forms. In the present study, the effect of indole-3-carbinol (I3C) and 5,6-benzoflavone (5,6BF) on the expression of cytochrome P450IA1 in rat colon and liver has been investigated. Cytochrome P450IA1 mRNA was induced in colon following a single oral administration of I3C or 5,6BF. A biphasic induction profile was obtained with maxima at 4 and 16 h post-administration. Both inducers caused an approximately 2-fold increase in P450IA1 mRNA at 4 h and a 10-fold increase at 16 h. In contrast, both cytochrome P450IA1 and IA2 mRNAs was increased over the control between 4 and 24 h. The total amount of P450IA mRNAs in liver at 4 and 16 h was increased about 2- and 4-fold respectively by I3C; 5,6BF induced the P450IA mRNAs 4- and 5-fold respectively. The expression of cytochrome P450IA1 and IA2 is induced by I3C and several flavones present in cruciferous vegetables. This suggests that one of the protective effects of cruciferous vegetables in the reduction of chemically induced cancer may be regulation of cytochrome P450s involved in the metabolism of the chemical carcinogens.

Animals↗
PubMed1990

Biological monitoring of foundry workers exposed to polycyclic aromatic hydrocarbons.

This investigation describes benzo(a)pyrene (BP) serum protein adduct concentrations in 45 foundry workers and 45 matched non-occupationally exposed controls. High and low BP exposure groups were defined using breathing zone hygienic samples for both quartz and BP exposures. A newly developed enzyme linked immunosorbent assay detected benzo(a)pyrenediolepoxide-I binding to serum protein. Mean BP protein adduct concentrations (SD) for non-smoking (24.0 BP equivalents/100 micrograms protein (21.0] and smoking (28.0 (18.2] foundry workers were significantly higher than mean values for non-smoking (7.23 (8.72] and smoking (14.2 (24.4] controls. Foundry workers with high exposures to either quartz (28.4 (15.5] or BP (30.7 (19.3] had slightly raised mean adduct concentrations compared with foundry workers with low exposure for quartz (23.9 (23.1] or BP (24.5 (19.4). Highest mean adduct concentrations were found among a small group of workers with simultaneous high exposures to both quartz and BP (39.2 (6.5] suggesting an additive effect. These data support the ideas of a possible aetiological connection between an increased risk of lung cancer and BP exposure among foundry workers, and an additive effect between BP and quartz. Measurement of BP serum protein adduct concentrations appears to be a useful method by which groups exposed to BP may be biologically monitored.

Adult↗
PubMed1989

Endogenous nitrosation in relation to nitrate exposure from drinking water and diet in a Danish rural population.

Increasing levels of nitrate in drinking water is of concern due to the possibility of an associated increase in long-term exposure to endogenously formed carcinogenic N-nitroso compounds. Excretion of N-nitrosoproline in 12-h overnight urine after intake of 500-mg L-proline was used to quantify the rate of endogenous nitrosation in 285 individuals in an area in northern Denmark with large variation in nitrate concentration of the drinking water. Nitrate intake was measured in a 24-h duplicate diet sample. The crude association between nitrate concentration in drinking water and rate of endogenous nitrosation in individuals is only weakly positive and not quite statistically significant (P = 0.08). The risk of having detectable nitrosation increases significantly with total nitrate intake and tobacco smoking. In nonsmokers, nitrosation is determined by nitrate intake. Smokers have increased nitrosation which does not depend on nitrate intake. Effect modification through dietary factors was evaluated and indicated a protective effect of tea consumption, while the effect of eating vegetables was not clear-cut. The experimental design (12-h urine sample; proline dose taken in the evening) is likely to underestimate the effect of nitrate in drinking water relatively to nitrate in the diet.

Denmark↗
PubMed1989

Malignant transformation of human bladder epithelial cells by DNA transfection with the v-raf oncogene.

Transfection of the v-raf oncogene into immortalized, nontumorigenic human bladder epithelial cells resulted in the isolation of two tumorigenic transformants. Both were identified as human and of the same origin as the parent cell line by human leukocyte antigen typing and Southern blot analysis. Both the primary tumorigenic transfectants and the cell lines established from the induced tumors expressed v-raf mRNA and v-raf protein. In both tumorigenic transformants the level of c-myc mRNA was enhanced compared with that of the parent cell line.

Animals↗
PubMed1989

Nitrate exposure from drinking water and diet in a Danish rural population.

Increasing levels of nitrate (NO3-) in drinking water in Denmark is of concern due to the possibility of an associated increase in long-term exposure to endogeneously formed N-nitroso compounds. Using a duplicate portion technique in combination with a qualitative description of diet and other background variables, the total nitrate intake in a Danish rural population and the contribution of drinking water to the total nitrate exposure is estimated. People drinking nitrate-free water have an intake of 37 mg NO3- per day. At 47 mg NO3- per litre, the exposure is increased to 89 mg, about 60% of which originates from the water. At 84 mg NO3- per litre, the daily exposure is 123 mg, 70% of which originates from the drinking water. These crude comparisons between three groups of people are supplemented with quantitative modelling of nitrate exposure at individual level. Apart from drinking water, consumption of vegetables is a major source of nitrate in this population. Using nitrate in overnight urine samples to quantify exposure is less accurate than the duplicate dietary portion technique and tends, in the present study, to underestimate the contribution of water-derived nitrate to total nitrate intake.

Adult↗
PubMed1988

Induction of cytochrome P-450IA1 gene expression in human breast tumour cell lines.

The induction of cytochrome P-450IA1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was studied in eight human breast tumour cell lines. The cells were treated with various concentrations of TCDD for 24 h, and total RNA was isolated. The level of P-450IA1 RNA induced by 1 nM TCDD followed the order: MCF-7 greater than T47-D greater than ZR-75-1 greater than 3909 greater than 3522. AL-1, BT-20 and CAMA-1 did not respond to TCDD at the concentrations used. Northern blot analysis revealed 2 bands at 2.7 and 2.0 Kb, respectively, with the larger band being 6-fold more intense. The ratio was not changed by the TCDD treatment. TCDD induction did not change the benzo[a]pyrene-7,8-diol (BP-7,8-diol) metabolite profile compared with control cells, when cells were incubated with [3H]BP-7,8-diol for 24 h following the treatment with TCDD. These results demonstrate that different breast tumour cell lines vary greatly with respect to the basal expression levels of P-450IA1 RNA and its inducibility by TCDD. Furthermore, TCDD treatment does not change the relative distribution of BP-7,8-diol metabolites.

Breast Neoplasms↗
PubMed1988

Substances with affinity to a monoclonal aflatoxin B1 antibody in Danish urine samples.

Using a competitive enzyme immunoassay, one or more substances recognized by a monoclonal antibody against aflatoxin B1 were detected in human urine samples collected in Denmark. The concentration of urinary aflatoxin-like substances was equivalent to 0.0-6.5 ng aflatoxin B1/mg creatinine. A truly competitive interaction in the immunoassay was found between aflatoxin-like substances and aflatoxin B1. Aflatoxin-like substances could be isolated in small quantities from urine by affinity chromatography. The quantity of urinary aflatoxin-like compounds in the samples collected showed a skewed normal distribution (80 individuals). In order to explain the seemingly high level of aflatoxin-like material in urine samples from people living in a cold temperate climate, the source of aflatoxin-like compounds was investigated. In a dietary restriction study, potential dietary factors leading to excretion of aflatoxin-like compounds were investigated. Our data indicate that the excretion of these compounds by healthy Danes depends mainly on the food ingested 24-48 hr before urine samples were collected. In particular, the excretion of aflatoxin-like substances was increased when diets include beer, dairy products or meat. A map of the epitope recognized by the antibody was constructed from the results of competition studies with several AFB1 analogues. The epitope map was used to draw chemical structures representing the minimal requirements for antibody recognition. An on-line search was conducted among the 98.2 x 10(6) structures in the Chemical Abstracts and Registry Databases (STN, Columbus, OH) and provided strong evidence that only aflatoxins or aflatoxin derivatives are recognized by the antibody. The possible chemical structures of the aflatoxin-like substances are discussed.

Aflatoxin B1↗
PubMed1988

Cancer risk and occupational exposure to aflatoxins in Denmark.

A study of cancer risk among male employees at 241 livestock feed processing companies in Denmark was conducted on the basis of a data linkage system for detailed investigation of occupational cancer providing employment histories back until 1964, established at the Danish Cancer Registry. Crops imported for feed production have often been contaminated with highly variable concentrations of aflatoxins; an estimated average concentration of at least 140 micrograms aflatoxin B1 kg-1 prepared mixed cattle feed prevailed in the past, yielding a daily intake for workers via the respiratory route of approximately 170 ng. Risk was established on the basis of cancer cases among male workers, whose employment in one of the companies was the job they had held for the longest time since 1964. Elevated risks for liver cancer and for cancers of the biliary tract were observed, which increased by two- to three-fold significance after a 10-year latency. Exposure to aflatoxins in the imported crops was judged to be the most probable explanation for these findings, although the influence of lifestyle factors, e.g. alcohol consumption on the results cannot be fully disregarded. Increased risks for salivary gland tumours and multiple myeloma were also detected. However, due to multiple comparisons carried out in this study these new associations must await further confirmation. A decreased risk for lung cancer was observed; despite possible negative confounding due to the smoking habits of the employees, the lung does not seem to be a target organ for the carcinogenic effect of inhaled aflatoxins in humans.

Adult↗
PubMed1988

Detection of exposure to aflatoxin in an African population.

Urinary excretion of 8,9-dihydro-8-(7'-guanyl)-9-hydroxyaflatoxin (AFB-Gua) was studied in areas of different liver cancer incidence in Kenya. Of 983 urine samples analysed for AFB-Gua by high-performance liquid chromatography, 12.6% gave positive results. The chemical identity of AFB-Gua was verified by synchronous scanning fluorescence spectrophotometry. A moderate degree of correlation between prevalence of exposure to aflatoxin B1 and liver cancer incidence could be established in Bantu. People living in areas with high exposure to aflatoxin B, form antibodies that recognize an aflatoxin B1 epitope.

Aflatoxin B1↗
PubMed1987

Aflatoxin exposure measured by urinary excretion of aflatoxin B1-guanine adduct and hepatitis B virus infection in areas with different liver cancer incidence in Kenya.

Two major etiological agents, hepatitis B virus and aflatoxin B1, are considered to be involved in the induction of liver cancer in Africa. In order to elucidate any synergistic effect of these two agents we conducted a study in various parts of Kenya with different liver cancer incidence in order to establish the rate of exposure to aflatoxin and the prevalence of hepatitis infections. Of all tested individuals 12.6% were positive for aflatoxin exposure as indicated by the urinary excretion of aflatoxin B1-guanine. Assuming no annual and seasonal variation, a regional variation in the exposure was observed. The highest rate of aflatoxin exposure was found in the Western Highlands and Central Province. The incidence of hepatitis infection nationwide as measured by the presence of the surface antigens was 10.6%, but a wide regional variation was observed. A multiplicative and additive regression analysis to investigate if hepatitis and aflatoxin exposure had a synergetic effect in the induction of liver cancer was negative. However, a moderate degree of correlation between the exposure to aflatoxin and liver cancer was observed when the study was limited to certain ethnic groups. The study gives additional support to the hypothesis that aflatoxin is a human liver carcinogen.

Aflatoxin B1↗
PubMed1987

Differential induction of transcription of c-myc and c-fos proto-oncogenes by 12-O-tetradecanoylphorbol-13-acetate in mortal and immortal human urothelial cells.

The effect of the skin tumor-promoter TPA (12-O-tetradecanoylphorbol-13-acetate) on expression of cellular proto-oncogenes has been examined in cell lines derived from human urothelium. A single treatment with TPA (1 microgram/ml) increased the transcription of c-fos and c-myc proto-oncogenes at least 20-fold in the mortal cell line HU 1752. The induction was transient and was accompanied by a rapid but transient change in cell morphology. When immortalized cell lines were treated with TPA a similar rapid and transient morphological response was observed, but the TPA treatment only increased the level of c-fos mRNA, suggesting that the normal regulation of c-myc transcription is altered in immortalized cells irrespective of their tumorigenic properties. The levels of c-Ha-ras and c-Ki-ras mRNAs were unaffected by TPA treatment in all cell lines.

Cell Line↗
PubMed1986

Genomic 5-methylcytosine determination by 32P-postlabeling analysis.

A simple and sensitive method for the quantitation of 5-methyldeoxycytidine in DNA has been developed by the adaptation of the Randerath 32P-postlabeling technique. Nucleic acids were digested to 3'-monophosphate nucleotides, which were converted to 32P-labeled 3',5'-bisphosphate nucleotides, the 3'-phosphate was cleaved by the action of nuclease P1, and the resultant 5'-[32P]-monophosphate nucleotides were separated by two-dimensional thin-layer chromatography. Less than 1 microgram of DNA was required for the precise quantitation of 5-methyldeoxycytidine content to a detectable limit of 0.01% of the total cytidine residues methylated. The genomic 5-methyldeoxycytidine content may thus be quantitated in tissue samples, small or selective cell populations, senescing or terminally differentiating cells, or DNA from any source. We report here, for the first time, the genomic 5-methyldeoxycytidine content of normal human bronchial epithelial and normal human pulmonary mesothelial cells. The chromatographic separation of all of the normal and some of the rare monophosphate deoxyribonucleotides and ribonucleotides has been characterized. Thus, 5-bromodeoxyuridine and the RNA contamination of DNA or the DNA contamination of RNA can also be quantitated during the same analysis.

5-Methylcytosine↗
PubMed1986

Inter-individual variations in carcinogen metabolism.

Explant cultures of human tissues metabolized chemical carcinogens into the ultimate carcinogenic form as measured by binding to cellular DNA. A wide inter-individual variation in the binding level of many chemical carcinogens to target cell DNA was observed, whereas lesser inter-individual variation was observed in primary epithelial cell cultures derived from the explants. The binding levels in the explants showed a unimodal distribution without any sub-populations being present. The binding level of benzo(a)pyrene to human bronchial DNA has been analyzed with respect to genetic and environmental factors such as family history of cancer and smoking history.

Benzo(a)pyrene↗
PubMed1986

Excretion of benzo[a]pyrene-Gua adduct in the urine of benzo[a]pyrene-treated rats.

A benzo[a]pyrene(BP)-Gua adduct was extracted in the urine of rats treated with BP. Some (0.15%) of the administered dose of BP was excreted as BP-Gua within 48 h. A double labelling experiment demonstrated that the excreted product contained both a BP and a Gua moiety. Partially hepatectomized rats treated with [14C]Gua during the regenerative phase were injected with [3H]BP and the urine collected and processed by chromatographic procedures. The adduct had similar chromatographic properties to the adduct released from human PLC/5 cells treated with 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) and co-chromatographed with 7-BPDE-Gua released from BPDE-adducted DNA under aqueous conditions. Detection and quantitation of BP-Gua offers an alternative, non-invasive method of monitoring individuals exposed to carcinogenic polycyclic aromatic hydrocarbons (PAHs).

Animals↗