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Biomedical subjects

Klaus Golka

Publications and source records attributed to Klaus Golka.

At least 19 recordsLinked to original sources
PubMed2006

Glutathione S-transferase polymorphisms and ochratoxin A toxicity in primary human urothelial cells.

The mycotoxin ochratoxin A (OTA) is a worldwide contaminant of human food. OTA is genotoxic, immunotoxic, teratogenic and carcinogenic in rodents and can cause nephropathy in pigs. High amounts of OTA can cause nephropathy in humans. Moreover, evidence has been accumulated that OTA is a genotoxic carcinogen. Nevertheless, the mechanism that leads to OTA toxicity has not been fully resolved and it is discussed if a bioactivation of OTA is necessary or not. In this study the genotoxicity of OTA was investigated in primary human urothelial cells by means of alkaline single cell gel electrophoresis (Comet assay). Primary cultured human urothelial cells derived from tissue specimens of urological patients were incubated with 100 microM OTA for 3 h. In contrast to recently published results in MDCK cell lines, the cell cultures showed great interindividual differences in the extent of DNA damage. To evaluate these great interindividual differences the influence of the genotype of the isoenzymes of glutathione S-transferase (GST), namely GSTT1, GSTM1 and GSTP1 on the genotoxic potential of OTA was examined. The genotypes of these polymorphic enzymes were determined by polymerase chain reaction (PCR) and the distributions of the genotypes were correlated with the extent of DNA damage. We found associations between the genotypes of the polymorphic GST isoenzymes and the extent of DNA damage between subgroups with and without OTA-related DNA damage. From these results we conclude that genetic predisposition has the potential to influence OTA genotoxicity.

Aged↗
PubMed2006

From neurotoxic to chemosensory effects: new insights on acute solvent neurotoxicity exemplified by acute effects of 2-ethylhexanol.

Historically, acute solvent neurotoxicity was strongly related to reversible narcotic states that could be detected by neurobehavioral tests (e.g., simple reaction time). Nowadays, the occupational exposure to chemicals is markedly reduced and the avoidance of chemosensory effects is more important for the regulation of solvents. Exemplarily, this study examines if the chemosensory perception of 2-ethylhexanol is capable to distract performance in demanding neurobehavioral tasks. In two experiments three time-weighted average concentrations of 2-ethylhexanol (C(TWA): 1.5, 10, and 20 ppm) were investigated. In experiment A (n=24) variable concentrations over time (4h) were used, experiment B (n=22) investigated constant concentrations. The experiments were conducted in a 29 m3 exposure laboratory. Cross-over designs with randomized sequences of exposures were used. Among the 46 male participants 19 subjects reported enhanced chemical sensitivity; the other 27 subjects did not show this personality feature. During the exposure periods neurobehavioral tests were presented twice (beginning; end), the intensity of chemosensory perceptions were rated thrice. The intensity of chemosensory perceptions showed a clear dose-dependency. Subjects' performance in the vigilance test was not affected by the different exposures. Moreover, the results of neurobehavioral tests measuring executive function were neither affected by the C(TWA) concentration nor by the exposure peaks. With increasing C(TWA), a subgroup of the chemically sensitive subjects showed deteriorated accuracy in a divided attention task. Especially the 20 ppm conditions were very annoying. Only during the constant 10 ppm condition the time courses of the annoyance and nasal irritation ratings indicated some adaptation. In general, with the applied neurobehavioral tests distractive effects of acute 2-ethylhexanol exposures up to 20 ppm could not be confirmed. In sensitive groups such distractive effects of irritating solvents might be conceivable and moreover, in cooperation with researchers from cognitive neuroscience more sensitive functions and tests should be developed and incorporated.

Adult↗
PubMed2006

Arsenic-related skin lesions and glutathione S-transferase P1 A1578G (Ile105Val) polymorphism in two ethnic clans exposed to indoor combustion of high arsenic coal in one village.

OBJECTIVES: A total of 2402 patients with arsenic-related skin lesions, such as hyperkeratosis, hyperpigmentation or hypopigmentation, or even skin cancer in a few villages in Southwest Guizhou Autonomous Prefecture, China represent a unique case of endemic arsenism related with indoor combustion of high arsenic coal. This study aimed to investigate the cluster of arsenism cases and the possible relevant factors including GSTP1 polymorphism in two clans of different ethnic origin living in one village for generations. METHODS: A questionnaire-based study was performed in 170 Miao clan P members, 10 of whom had arsenic-related skin diseases, and 153 Han clan G1 members, 50 of whom had arsenic-related skin diseases. The data were checked against the registration archives since the 1980s. At the same time, arsenic concentrations in samples of coal, indoor air, drinking water, corn and chilli pepper that were once baked over the stoves for desiccation, as well as in samples of urine and hair of clan members were determined. Glutathione S-transferase P1 (GSTP1) A1578G polymorphism was genotyped by a restriction fragment length polymorphism-based procedure. RESULTS: Arsenism morbidity in Miao clan P was significantly lower than in the neighbouring Han clan G1 [5.9 vs. 32.7%, odds ratio (OR)=0.13, 95% confidence interval (CI): 0.06-0.27, P<0.0001]. No sex differences were confirmed inside both clans. Analyses of the environmental samples indicated that Miao clan P members were exposed to higher amounts of arsenic via inhalation and food ingestion. Hair and urine samples also proved a higher arsenic body burden in ethnic Miao individuals. No corresponding differences by sex were found. Higher frequencies of combined mutant genotype G/G1578 and A/G1578 (OR=4.72, 95% CI: 2.34-9.54, P<0.0001) and of mutant allele G1578 (OR=3.22, 95% CI: 2.00-5.18, P<0.0001) were detected in diagnosed arsenism patients than in non-diseased individuals. The Miao individuals showed a lower percentage of combined mutant genotypes (30.6 vs. 52.7%, OR=0.40, 95% CI: 0.19-0.84, P=0.015) as well as of mutant allele G1578 (OR=0.46, 95% CI: 0.24-0.88, P=0.017) than their Han neighbours. CONCLUSIONS: Genetic predisposition influences dermal arsenism toxicity. The GSTP1 A1578G (Ile105Val) status might be a susceptibility factor for arsenic-related skin lesions.

Adolescent↗
PubMed2004

An association of UDP-glucuronosyltransferase 2B7 C802T (His268Tyr) polymorphism with bladder cancer in benzidine-exposed workers in China.

UDP-Glucuronyltransferase 2B7 (UGT2B7) is involved in benzidine metabolism, as demonstrated by in vitro experiments with liver slices. To evaluate the possible association of UGT2B7 gene polymorphism with bladder cancer risk for benzidine-exposed subjects, diagnosed bladder cancer cases (n = 36) who were members of a cohort of benzidine-exposed workers in the Chinese dyestuff industry were investigated. UGT2B7 polymorphism at locus C802T (His268Tyr) was detected using a PCR-RFLP based procedure. Nondiseased cohort members (156 men, 95 women) were taken as work-related control, and unexposed healthy individuals (113 men, 105 women) were taken as community control. The data showed that the polymorphism at locus UGT2B7 C802T in a general Chinese population significantly differs from that in a Caucasian population (p = 0.00018), displaying a distinctly lower frequency of T/T genotypes (9.2 vs. 25.3%), while no significant difference to a Japanese population could be detected (p = 0.17). A higher prevalence of T/T genotype carriers was found in the cancer cases, compared with unexposed healthy controls (25 vs. 9%, odds ratio [OR] 3.30, 95% confidence interval [95% CI] 1.37-7.98, p = 0.006). A higher presentation of T allele carriers in the patients group was also confirmed (46 vs. 33%, OR 1.73, 95% CI 1.05-2.87, p = 0.03). A higher portion of the T/T genotype was also observed in bladder cancer patients compared with nondiseased members of the same benzidine-exposed cohort, although some of them displayed different degrees of cellular alterations in their exfoliated urothelial cells. This study points for the first time to an association between a homozygous mutant genotype of human UDP-glucuronosyltransferase 2B7 catalyzing the biotransformation of benzidine and an elevated bladder cancer risk for formerly benzidine-exposed workers of the dyestuff industry.

Asian People↗
PubMed2004

Re-investigation of the concordance of human NAT2 phenotypes and genotypes.

A comparative study of N-acetyltransferase 2 (NAT2) genotyping and phenotyping (caffeine test method) was performed on 211 persons to elucidate apparent discrepancies in the assignment of NAT2*12 and NAT2*13 alleles which occur in the literature. The study used the standard procedures of genotyping (two PCR runs and application of seven restriction enzymes) and phenotyping (determination of the two caffeine metabolites 5-acetylamino-6-formylamino-3-methyluracil (AFMU) and 1-methylxanthine (1X)), as documented in detail and validated by the Deutsche Forschungsgemeinschaft. The data were consistent with an AFMU/1X molar ratio of 0.85 as cut-off point (antimode) between phenotypically slow and rapid acetylators. Under this provision, several R/S allele combinations did not comply, either fully or partly, with their associated phenotypes. In particular, there was a wide phenotypic overlap of the alleged rapid allele combination groups (i) NAT2*12A/*5A; NAT2*12C/*5D; NAT2*4/*5B, (ii) NAT2*13/*6B; NAT2*4/*6A, and (iii) NAT2*13/*7A; NAT2*4/*7B. These groups obviously contained both phenotypically rapid and slow acetylators. If one assumes that the presence of one "wild type" allele NAT2*4 defines a rapid acetylator the assignment of the alleles NAT2*12A, NAT2*12C, and NAT*13 as determinants of a rapid acetylator phenotype must be questioned. This refers in particular to the nucleotide changes A803G (NAT2*12A, NAT2*12C) and C282T (NAT2*13). Based on discussions in the literature and the data presented here, there is accumulating evidence that current assignments of the NAT2*12 and NAT2*13 alleles as determinants of a rapid acetylator state should be reconsidered.

Acetylation↗
PubMed2004

Primary testicular carcinoid.

BACKGROUND: Testicular tumors in general can be classified as seminoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, and mixed tumors. Nevertheless, other histological types may also be observed. In rare cases, primary or secondary neuroendocrine tumors derived from chromaffine cells can be observed in the testicle. CASE REPORT: A 51-year-old patient was hospitalized on account of a two-month-old painless tumescence of the right testicle. Radical orchiectomy revealed a solid, inhomogeneous intratesticular tumor 3 cm in diameter. Pathohistological findings and immunohistochemical staining with different neuroendocrine markers revealed a testicular carcinoid classified as pT1. The excretion of 5-hydroxyindole-acetic acid (5-HIAA) was within the normal range. No further carcinoid tumor site was found. CONCLUSIONS: In case of a testicular carcinoid, exclusion of a primary carcinoid tumor site in other organs is mandatory.

Carcinoid Tumor↗
PubMed2004

Comparative metabolic activation of benzidine and N-acetylbenzidine by prostaglandin H synthase.

Benzidine and N-acetylbenzidine are activated to genotoxic metabolite(s) within the urothelial target tissue, with phase-I and phase-II enzymes being relevant. In principle, both benzidine and N-acetylbenzidine are activated by prostaglandin H synthase (PHS) to reactive intermediates. However, the relative impacts of benzidine and N-acetylbenzidine in this process remain unclear. Two experimental in vitro systems were used in the present comparative investigation: ram seminal vesicle microsomes rich in PHS and porcine urinary bladder epithelial cells (PUBEC) as a model system mimicking the general metabolic situation within the human urothelium. Benzidine, N-acetylbenzidine and N,N'-diacetylbenzidine were incubated with ram seminal vesicle microsomes and arachidonic acid and control incubations were performed with heat-inactivated microsomes. The metabolic disappearance of benzidine, N-acetylbenzidine or N,N'-diacetylbenzidine indicated a rapid turnover by PHS of benzidine and a slower turnover of N-acetylbenzidine. There was almost no PHS-associated metabolism of N,N'-diacetylbenzidine, suggesting that diacetylation of benzidine could represent a pathway of biological inactivation. Under similar conditions, incubations were performed with ram seminal vesicles and benzidine or N-acetylbenzidine upon addition of calf thymus DNA. After re-isolation of the DNA and 32P-postlabeling, with benzidine 2 distinct adducts were found of unknown nature, and with N-acetylbenzidine a single adduct appeared with co-migrated with the N'-(3'-monophosphodeoxyguanosin-8-yl)-N-acetylbenzidine. PUBEC cells were also incubated with benzidine or N-acetylbenzidine. No DNA adduct was found with benzidine, but a total of five adducts was produced from N-acetylbenzidine. The major adduct again co-migrated with N'-(3'-monophosphodeoxyguanosin-8-yl)-N-acetylbenzidine. When benzidine was incubated with PUBEC cells N-acetylbenzidine and, with some delay, N,N'-diacetylbenzidine were formed. Application of Lineweaver-Burk plots for the formation of N-acetylbenzidine from benzidine revealed a K(m) of 56.4 microM and a Vmax of 7.05 nmol/h per 10(6) PUBEC cells. The investigations generally support a key role of N-acetylbenzidine at the target site of the urothelium.

Animals↗
PubMed2004

Carcinogenicity of azo colorants: influence of solubility and bioavailability.

In the past, azo colorants based on benzidine, 3,3'-dichlorobenzidine, 3,3'-dimethylbenzidine (o-tolidine), and 3,3'-dimethoxybenzidine (o-dianisidine) have been synthesized in large amounts and numbers. Studies in exposed workers have demonstrated that the azoreduction of benzidine-based dyes occurs in man. The metabolic conversion of benzidine-, 3,3'-dimethylbenzidine- and 3,3'-dimethoxybenzidine-based dyes to their (carcinogenic) amine precursors in vivo is a general phenomenon that must be considered for each member of this class of chemicals. Several epidemiological studies have demonstrated that the use of the benzidine-based dyes has caused bladder cancer in humans. However, in contrast to water-soluble dyes, the question of biological azoreduction of (practically insoluble) pigments has been a matter of discussion. As a majority of azo pigments are based on 3,3'-dichlorobenzidine, much of the available experimental data are focused on this group. Long-term animal carcinogenicity studies performed with pigments based on 3,3'-dichlorobenzidine did not show a carcinogenic effect. The absence of a genotoxic effect has been supported by mutagenicity studies with the 3,3'-dichlorobenzidine-based Pigment Yellow 12. Studies in which azo pigments based on 3,3'-dichlorobenzidine had been orally administered to rats, hamsters, rabbits and monkeys could generally not detect significant amounts of 3,3'-dichlorobenzidine in the urine. It, therefore, appears well established that the aromatic amine components from azo pigments based on 3,3'-dichlorobenzidine are practically not bioavailable. Hence, it is very unlikely that occupational exposure to insoluble azo pigments would be associated with a substantial risk of (bladder) cancer in man. According to current EU regulations, azo dyes based on benzidine, 3,3'-dimethoxybenzidine and 3,3'-dimethylbenzidine have been classified as carcinogens of category 2 as "substances which should be regarded as if they are carcinogenic to man". This is not the case for 3,3'-dichlorobenzidine-based azo pigments.

Animals↗
PubMed2004

Neurobehavioral effects of experimental exposures to low levels of styrene.

Two experimental studies were conducted with the intention to simulate exposure characteristics of work places with styrene exposure and to investigate the risk for neurobehavioral impairments. In experiment I 16 volunteers (8 in the morning, 8 in the afternoon) were exposed to 0.5 and 20 ppm styrene on a constant level for 3h. In experiment II 24 volunteers (12 in the morning, 12 in the afternoon) were exposed for 4h to 0.5 and 20 ppm styrene on a constant level as well as to a changing exposure between 0.5 and 40 ppm with a TWA of 14 ppm. Simple reaction, choice reaction, attention, acute symptoms, and ratings for well-being were measured. Exposure related performance effects could not be detected. However, 6h time change resulted in delayed choice reactions in the morning hours. Analysing acute symptoms and the state of well-being the impact of styrene did not reach adverse extents of impaired well-being.

Adult↗
PubMed2004

1,3-Propane sultone, an extremely potent experimental carcinogen: what should be expected in humans?

1,3-Propane sultone is directly alkylating, genotoxic and carcinogenic. In rats, it induces local and systemic tumours at multiple target sites. Preponderant systemic tumours occur at the central nervous system, especially gliomas. Other localisations include the mammary gland, the intestine, the haematopoietic system and the kidneys. In the German chemical industry, 1,3-propane sultone had been manufactured and used in limited amounts in the 1950s and 1960s, and for a very few purposes until the 1970s. The number of persons in contact with the compound is unknown but was limited. The medical history of some cases could be traced. As cerebral gliomas are the main systemic tumours induced by 1,3-propane sultone experimentally, the occurrence of a glioblastoma among previously exposed persons appears conspicuous. Three intestinal malignancies were recorded among the cases observed. Also noteworthy is one case of a duodenal carcinoma, normally a rare human malignancy. Two haematopoietic/lymphatic malignancies of different nature have been observed, and there was one case of a renal cell carcinoma. These malignancies observed within a group of persons exposed to 1,3-propane sultone appear surprisingly consistent with the expectations from the available animal studies. The present case studies point to long latency times (up to 30-40 years or more) after limited periods of past exposure.

Brain Neoplasms↗
PubMed2004

Carbohydrate-deficient transferrin (CDT) as a biomarker in persons suspected of alcohol abuse.

The coherence of carbohydrate-deficient transferrin (CDT) as a biomarker of alcohol abuse was investigated with 15 conventional laboratory parameters, with the self-reported medical history and with clinical findings, all previously reported to be associated with chronic alcohol intake. In total, 100 male persons who were at least suspected of abusing alcohol were assessed. Medical history, clinical picture and physical examination were taken, and laboratory parameters regarding blood count, liver enzymes, serum lipids, iron balance, Ig A and uric acid were determined. These data were correlated with the CDT values, the daily ethanol intakes reported, and several findings from medical history and clinical examination. The mean CDT level (mean+/-S.D.) of the entire group was 29.4+/-19.7 U/l. Eighty-one patients admitted a daily ethanol intake of 60 g or more. The ratio AST/ALT (de Ritis ratio) appeared as the best conventional parameter correlated with both CDT and ethanol intake. Mean corpuscular volume (MCV), serum iron, AST and red blood cell count also correlated significantly with CDT. CDT, AST and ferritin correlated significantly with the reported daily ethanol intake. It is concluded that CDT provides a reliable estimate of long-term alcohol intake.

Adult↗
PubMed2004

Association of metabolic gene polymorphisms with tobacco consumption in healthy controls.

Polymorphisms in genes that encode for metabolic enzymes have been associated with variations in enzyme activity between individuals. Such variations could be associated with differences in individual exposure to carcinogens that are metabolized by these genes. In this study, we examine the association between polymorphisms in several metabolic genes and the consumption of tobacco in a large sample of healthy individuals. The database of the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens was used. All the individuals who were controls from the case-control studies included in the data set with information on smoking habits and on genetic polymorphisms were selected (n = 20938). Sufficient information was available on the following genes that are involved in the metabolism of tobacco smoke constituents: CYP1A1, GSTM1, GSTT1, NAT2 and GSTP1. None of the tested genes was clearly associated with smoking behavior. Information on smoking dose, available for a subset of subjects, showed no effect of metabolic gene polymorphisms on the amount of smoking. No association between polymorphisms in the genes studied and tobacco consumption was observed; therefore, no effect of these genes on smoking behavior should be expected.

Arylamine N-Acetyltransferase↗
PubMed2004

Polymorphism in the N-acetyltransferase 1 alleles NAT1*10 and NAT1*14A and cytological gradings of exfoliated urothelial cells in benzidine-exposed Chinese workers: discussion of ethnic differences.

N-acetyltransferase 1 (NAT1) modifies bladder cancer risk in European populations exposed to aromatic amines in cigarette smoke. The present study was performed to investigate a possible association between NAT1*10 and NAT1*14A genotypes and bladder cancer risk in benzidine-exposed Chinese workers. Based on the cytological gradings of exfoliated urothelial cells according to Papanicolaou, an exposed research cohort was stratified into subgroups. An allele-specific PCR-based procedure was used to detect the polymorphism in the polyadenylation signal at the locus NAT1 T(1088)A. A nested PCR-RFLP procedure was conducted to differentiate NAT1*14A (T(1088)A, C(1095)A, and G(560)A) from NAT1*10 (T(1088)A, C(1095)A). No significantly different frequencies of homozygous and heterozygous NAT1*10 alleles were found among the subgroups with (i) gradings according to Papanicolaou < or = II (18.3 and 40.2%, respectively), (ii) higher gradings according to Papanicolaou (> II; 28.0 and 34.1%, respectively), and (iii) with bladder cancer (26.3 and 34.2%, respectively). The present data show that NAT1*10 neither displayed an association with an elevated grading of urothelial cells nor a clear impact on the risk for bladder cancer in benzidine-exposed Chinese workers. Discrepancies with the findings in European populations could point to ethnic differences in the disposition of aromatic amines.

Adult↗
PubMed2004

Polymorphism of N-acetyltransferase 2 (NAT2) gene polymorphism in shanghai population: occupational and non-occupational bladder cancer patient groups.

OBJECTIVE: Arylamine N-acetyltransferases (NATs) are involved in the detoxification of aromatic amines and hydrazine. In order to explore the possible association of NAT2 polymorphism with bladder cancer risk in benzidine exposed or non-exposed Chinese individuals, healthy subjects, subjects with bladder cancer of a former benzidine exposed cohort in Shanghai dyestuff industry and a group of bladder cancer patients without known occupational exposure to aromatic amines were genotyped for NAT2 gene polymorphism. METHODS: NAT2 genotyping was performed with a set of RFLP procedures at seven major polymorphic loci of gene coding area: G191A, C282T, T341C, C481T, G590A, A803G and G857A. RESULTS: The wild allele NAT2 *4 was the most prevalent allele (59%) in healthy individuals. The alleles NAT2*6A and NAT2*7B were also frequently observed (21% and 17%, respectively). In contrast to Caucasians, the percentage of slow acetylators was lower (12% in Chinese vs. 58% in Caucasians, P < 0.001). No relevant differences were observed for homogenous rapid, heterogeneous rapid/slow and homogeneous slow acetylation genotypes between the healthy subjects and both groups of bladder cancer patients. CONCLUSION: The present work did not support the association of slow acetylating genotypes of NAT2 gene with elevated risk of bladder cancer in Chinese whereas it was documented as an important genetically determined risk factor in Caucasians. Different mechanisms might play a role in individual susceptibility to bladder cancer related with aromatic amine exposure in various races or ethnic groups.

Arylamine N-Acetyltransferase↗
PubMed2003

Occupational exposure and urological cancer.

Occupational exposure is definitely a major cause of cancer. In the field of urology, the urinary bladder is the most important target. A classical cause of bladder cancer is exposure to carcinogenic aromatic amines, especially benzidine and beta-naphthylamine. Such exposures were related to work places in the chemical industry, implying production and processing of classical aromatic amines, and in the rubber industry. Occupational bladder cancer has also been observed in dyers, painters and hairdressers. Even some occupations with much lower exposures to carcinogenic aromatic amines, like coke oven workers or workers in the rubber industry after the ban on beta-naphthylamine, are at risk. In these occupations, exposure to complex mixtures of substances containing combustion products (e.g. polycyclic aromatic hydrocarbons) or nitrosamines is common. Renal cell cancer has been observed as an occupational disease in cases of very high exposure to trichloroethylene having led to narcotic or prenarcotic symptoms. Occupationally related cancers of the prostate or the testes appear currently not relevant.

Amines↗
PubMed2003

Breathing and heart rate during experimental solvent exposure of young adults with self-reported multiple chemical sensitivity (sMCS).

This paper deals with the assumption that young adults with self-reported multiple chemical sensitivity (sMCS) show a heightened sensitivity of autonomic functions during experimental solvent exposure. Male sMCS-subjects were selected (out of n=274) on the base of a German questionnaire on chemical and environmental sensitivity (CGES). Two independent experiments were carried out, each with 12 sMCS-subjects and 12 age-matched control-subjects. In experiment I two concentrations of the solvents ethyl benzene (10 and 98 ppm) and 2-butanone (10 and 189 ppm) were used. Experiment II investigated 2-propanol (35 and 190 ppm) and 1-octanol (0.1 and 6.4 ppm). The low concentrations correspond nearly to the olfactory thresholds while the high concentrations correspond to the German occupational threshold limit values (MAC). The exposure duration under each condition was 4h. The sequence of the four exposure conditions was random including intervals of at least 2 days without exposure. During the exposure physiological changes of breathing rate and heart rate were recorded. Two 30 min intervals with a sedentary position of the subjects at the beginning and end of exposure were chosen for analyses. Neither in experiment I nor in experiment II significant specific reactions to the type or level of the exposures were found. The autonomic functions in both experiments revealed alterations within the exposure sessions. The heart rate in experiment II and the breathing rate in both experiments decreased significantly during the analyzed 30 min intervals. Furthermore, in both experiments the heart rates decreased significantly from beginning to end of exposure. Only in experiment I the mean breathing rate of sMCS-subjects was generally higher compared to the control-subjects. Regarding the assumption of a heightened sensitivity of sMCS-subjects the two experiments yielded controversial results. Thus, the hypothesis of stronger responses of autonomic functions of sMCS-subjects provoked by various exposure scenarios remains open.

Adult↗
PubMed2003

Markers of genetic susceptibility in human environmental hygiene and toxicology: the role of selected CYP, NAT and GST genes.

Inherited genetic traits co-determine the susceptibility of an individual to a toxic chemical. Special emphasis has been put on individual responses to environmental and industrial carcinogens, but other chronic diseases are of increasing interest. Polymorphisms of relevant xenobiotic metabolising enzymes may be used as toxicological susceptibility markers. A growing number of genes encoding enzymes involved in biotransformation of toxicants and in cellular defence against toxicant-induced damage to the cells has been identified and cloned, leading to increased knowledge of allelic variants of genes and genetic defects that may result in a differential susceptibility toward environmental toxicants. "Low penetrating" polymorphisms in metabolism genes tend to be much more common in the population than allelic variants of "high penetrating" cancer genes, and are therefore of considerable importance from a public health point of view. Positive associations between cancer and CYP1A1 alleles, in particular the *2C I462V allele, were found for tissues following the aerodigestive tract. Again, in most cases, the effect of the variant CYP1A1 allele becomes apparent or clearer in connection with the GSTM1 null allele. The CYP1B1 codon 432 polymorphism (CYP1B1*3) has been identified as a susceptibility factor in smoking-related head-and-neck squameous cell cancer. The impact of this polymorphic variant of CYP1B1 on cancer risk was also reflected by an association with the frequency of somatic mutations of the p53 gene. Combined genotype analysis of CYP1B1 and the glutathione transferases GSTM1 or GSTT1 has also pointed to interactive effects. Of particular interest for the industrial and environmental field is the isozyme CYP2E1. Several genotypes of this isozyme have been characterised which seem to be associated with different levels of expression of enzyme activity. The acetylator status for NAT2 can be determined by genotyping or by phenotyping. In the pathogenesis of human bladder cancer due to occupational exposure to "classical" aromatic amines (benzidine, 4-aminodiphenyl, 1-naphthylamine) acetylation by NAT2 is regarded as a detoxication step. Interestingly, the underlying European findings of a higher susceptibility of slow acetylators towards aromatic amines are in contrast to findings in Chinese workers occupationally exposed to aromatic amines which points to different mechanisms of susceptibility between European and Chinese populations. Regarding human bladder cancer, the hypothesis has been put forward that genetic polymorphism of GSTM1 might be linked with the occurrence of this tumour type. This supports the hypothesis that exposure to PAH might causally be involved in urothelial cancers. The human polymorphic GST catalysing conjugation of halomethanes, dihalomethanes, ethylene oxide and a number of other industrial compounds could be characterised as a class theta enzyme (GSTT1) by means of molecular biology. "Conjugator" and "non-conjugator" phenotypes are coincident with the presence and absence of the GSTT1 gene. There are wide variations in the frequencies of GSTT1 deletion (GSTT1*0/0) among different ethnicities. Human phenotyping is facilitated by the GST activity towards methyl bromide or ethylene oxide in erythrocytes which is representative of the metabolic GSTT1 competence of the entire organism. Inter-individual variations in xenobiotic metabolism capacities may be due to polymorphisms of the genes coding for the enzymes themselves or of the genes coding for the receptors or transcription factors which regulate the expression of the enzymes. Also, polymorphisms in several regions of genes may cause altered ligand affinity, transactivation activity or expression levels of the receptor subsequently influencing the expression of the downstream target genes. Studies of individual susceptibility to toxicants and gene-environment interaction are now emerging as an important component of molecular epidemiology.

Arylamine N-Acetyltransferase↗