Biomedical subjects

H E Poulsen

Publications and source records attributed to H E Poulsen.

At least 19 recordsLinked to original sources

PubMed1995

Determination of ascorbic acid and dehydroascorbic acid in plasma by high-performance liquid chromatography with coulometric detection--are they reliable biomarkers of oxidative stress?

The concentrations of the hydrophilic antioxidants ascorbic acid and dehydroascorbic acid in plasma for some time have been considered possible biomarkers of oxidative stress. However, several problems are associated with the accurate measurement of these two compounds. We have developed and validated a selective and reproducible high-performance liquid chromatographic method for the quantification of ascorbic acid and dehydroascorbic acid in plasma. The method meets the requirements of a reliable routine analysis. The plasma samples are stabilized with 5 mM metaphosphoric acid, centrifugated at 4 degrees C before HPLC analysis. For ascorbic acid analysis, the sample pH is adjusted to 2.6, whereas for total ascorbic acid measurement dehydroascorbic acid is reduced to ascorbic acid using dithiothreitol for 5 min at pH 6.2 after which the sample pH is adjusted to 2.6. The samples are analyzed on a reversed-phase system using coulometric detection. Dehydroascorbic acid concentrations ae calculated by subtraction. Within- and between-day coefficients of variation for the complete assay were in the range of 4-8 and 3-6% for ascorbic acid and total ascorbic acid, respectively. The stability of ascorbic acid was monitored under various conditions including storage and the implications as well as the reliability of ascorbic acid as a biomarker are discussed.

Ascorbic Acid↗

PubMed1995

Early biochemical markers of effects: enzyme induction, oncogene activation and markers of oxidative damage.

Experimental carcinogenicity studies focus on identification of single carcinogens. Humans, however, appear exposed to a variety of low doses of carcinogens. Furthermore, few chemical entities are carcinogenic or toxic per se, but require metabolic activation to form ultimate carcinogens or toxins. In contrast to experimental animals, humans show considerable difference in genetic properties. In that situation it is particularly important to estimate individual capability for metabolic activation. To an increasing extent, activation includes formation of toxic oxygen metabolites. Particular targets for activated species are DNA and lipids; in particular low-density lipoproteins (LDL). Modifications of DNA are important for initiating the multistep process of carcinogenesis, in particular if oncogenes are activated or if tumor supressor genes are inactivated. Such DNA modification can be identical regardless of the reactive specimens being a xenobiotic or an oxygen species. Modification of LDL can start the process of atherosclerosis by transforming macrophages into foam cells, deposited as fatty streaks in the arterial wall. Biomarkers for activation capacity of xenobiotics include the use of prototype substrates and molecular techniques to determine genetic polymorphisms. Oxidative DNA modification can be measured from urinary excretion of oxidatively modified deoxynucleosides, particularly guanosine. Future efforts have to include individual measurements in order to improve the 'resolution' of molecular epidemiological approaches.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1995

Menadione-induced DNA fragmentation without 8-oxo-2'-deoxyguanosine formation in isolated rat hepatocytes.

Menadione (2-methyl-1,4-naphthoquinone) induces oxidative stress in cells causing perturbations in the cytoplasm as well as nicking of DNA. The mechanisms by which DNA damage occurs are still unclear, but a widely discussed issue is whether menadione-generated reactive oxygen species (ROS) directly damage DNA. In the present study, we measured the effect of menadione on formation of 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodG), an index of oxidative DNA base modifications, and on DNA fragmentation. Isolated hepatocytes from phenobarbital-pretreated rats were exposed to menadione, 25-400 microM, for 15, 90 or 180 min with or without prior depletion of reduced glutathione (GSH) by diethyl maleate. Menadione caused profound GSH depletion and internucleosomal DNA fragmentation, which was demonstrated by a prominent fragmentation ladder on agarose gel electrophoresis. We found no oxidative modification of DNA in terms of increased 8-oxodG formation. In contrast, the positive control of sunlamp light increased 8-oxodG 5-fold in rat hepatocytes. We conclude that oxidative modification of DNA bases is unlikely to be important in menadione-induced DNA damage.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1995

Restricted pulmonary diffusion capacity after exercise is not an ARDS-like injury.

Pulmonary diffusion capacity (DLCO) is reduced 2 h after various types of exercise, such as rowing, treadmill running, arm cranking and marathon running. The decrease in DLCO may involve alterations in the alveolar-capillary membrane as well as depletion of the central blood volume. We hypothesized that the reduction in DLCO might also be influenced by oxygen free radicals, acute phase proteins and endotoxin, which are also involved in the adult respiratory distress syndrome (ARDS). Ten competitive male oarsmen performed a 6 min 'all-out' ergometer row. Single breath DLCO was determined before and 2 h after rowing and venous blood samples were also obtained during the row. Absolute DLCO decreased by 11% (range 0-20%) 2 h after rowing, whereas the concentration of endotoxin did not change significantly and interleukin (IL)-1-alpha, IL-8 and tumour necrosis factor (TNF)-alpha were below the levels of detection before, during and 2 h after rowing. Oxygen free radicals were evaluated by oxidative modification of amino acids and DNA. Corrected for creatinine in urine voided 3 h post-exercise, the DNA repair product 8-oxo-7,8-dehydro-2-deoxyguanosine (8-oxodG) did not change significantly. The ratio of fluorescence due to dityrosine to that due to tryptophan in plasma proteins increased after exercise. This might reflect an effect of oxygen free radicals, but it might also indicate an altered relative composition of plasma proteins. These results suggest that the reduced pulmonary diffusion capacity following exercise is unrelated to factors typically associated with ARDS.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1995

Reduction of oxidative DNA-damage in humans by brussels sprouts.

The effect of consumption of Brussels sprouts on levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in human urine was investigated in 10 healthy, male, non-smoking volunteers. Following a 3 week run-in period, five volunteers continued on a diet free of cruciferous vegetables for a subsequent 3 week intervention period (control group), while the other five (sprouts group) consumed 300 g of cooked Brussels sprouts per day, at the expense of 300 g of a glucosinolate-free vegetable. Levels of 8-oxodG in 24 h urine samples were measured by HPLC. In the control group there was no difference between the two periods in levels of 8-oxodG (P = 0.72). In contrast, in the sprouts group the levels of 8-oxodG were decreased by 28% during the intervention period (P = 0.039). The present findings support the results of epidemiologic studies that consumption of cruciferous vegetables may result in a decreased cancer risk.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1995

Short-term moderate energy restriction does not affect indicators of oxidative stress and genotoxicity in humans.

Restriction of energy intake (ER), without malnutrition of essential nutrients, has repeatedly been demonstrated to increase longevity in rodents. In the antioxidant theory of aging the lack of balance between the generation of free radicals and free radical scavenging was thought to be a main causal agent, in the aging process. From this point of view the antiaging effect induced by ER might be due to the lower rate of free-radical production and related damage induced by a lower metabolic rate. The antiaging effects of ER might also occur in humans. This study explored the effects of a 10-week moderately energy-restricted diet (80% of habitual) in 24 non-obese middle-aged men (16 ER subjects, 8 controls) on resting metabolic rate (RMR) and indicators of the primary antioxidant defense system, oxidative stress and genotoxicity. RMR decreased significantly in both groups, even when adjustments were made for the change in body composition. The increase in blood vitamin C concentration correlated with the increase in urinary 8-hydroxydeoxyguanosine (80HdG) excretion. The change in urinary 80HdG excretion also correlated with the change in RMR per kg fat-free mass. No differences between groups were found for changes in indicators of genotoxicity, erythrocyte catalase, glutathione peroxidase and superoxide dismutase activity and in plasma vitamin E, A or beta-carotene concentrations. We conclude that 10 weeks of moderate ER did not affect indicators of antioxidative capacity, oxidative stress and genotoxicity of humans. Since subjects were not in energy balance at the end of the study, no conclusions can be made with respect to long-term effects.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1995

Selective serotonin reuptake inhibitors and theophylline metabolism in human liver microsomes: potent inhibition by fluvoxamine.

1. Fluvoxamine and seven other selective serotonin reuptake inhibitors (SRRI) were tested for their ability to inhibit a number of human cytochrome P450 isoforms (CYPs). 2. None of the drugs showed potent inhibition of CYP2A6 (coumarin 7-hydroxylase) or CYP2E1 (chlorzoxazone 6-hydroxylase), while norfluoxetine was the only potent inhibitor of CYP3A having IC50 values of 11 microM and 19 microM for testosterone 6 beta-hydroxylase and cortisol 6 beta-hydroxylase, respectively. 3. Norfluoxetine, sertraline and fluvoxamine inhibited CYP1A1 (7-ethoxyresorufin O-deethylase) in microsomes from human placenta (IC50 values 29 microM, 35 microM and 80 microM, respectively). Fluvoxamine was a potent inhibitor of CYP1A2-mediated 7-ethoxyresorufin O-deethylase activity (IC50 = 0.3 microM) in human liver. 4. In microsomes from three human livers fluvoxamine potently inhibited all pathways of theophylline biotransformation, the apparent inhibitor constant, Ki, was 0.07-0.13 microM, 0.05-0.10 microM and 0.16-0.29 microM for inhibition of 1-methylxanthine, 3-methylxanthine and 1,3-dimethyluric acid formation, respectively. Seven other SSRIs showed either weak or no inhibition of theophylline metabolism. 5. Ethanol inhibited the formation of 1,3-dimethyluric acid with K(i) value of 300 microM, a value which is consistent with inhibition of CYP2E1. Ethanol and fluvoxamine both inhibited 8-hydroxylation by about 45% and, in combination, the compounds decreased the formation of 1,3-dimethyluric acid by 90%, indicating that CYP1A2 and CYP2E1 are equally important isoforms for the 8-hydroxylation of theophylline. 6. It is concluded that pharmacokinetic interaction between fluvoxamine and theophylline is due to potent inhibition of CYP1A2.

Antidepressive Agents↗

PubMed1995

Kinetics and inhibition by fluvoxamine of phenacetin O-deethylation in V79 cells expressing human CYP1A2.

The kinetics of phenacetin O-deethylation and its inhibition by fluvoxamine was investigated in a V79 cell line (V79MZh1A2) transfected with human CYP1A2. In four sets of experiments the apparent Km values for phenacetin O-deethylation ranged from 35 to 95 microM and the Ki for fluvoxamine-mediated inhibition of the reaction ranged from 2.7 to 14.5 nM, i.e. comparable to values obtained in human liver microsomes. The kinetic performance of the V79MZh1A2 cell line demonstrates its usefulness as an analytical tool in a variety of toxicological and drug metabolism studies involving CYP1A2.

Acetaminophen↗

PubMed1995

Cytochrome P4502E1 inhibition by propylene glycol prevents acetaminophen (paracetamol) hepatotoxicity in mice without cytochrome P4501A2 inhibition.

Acetaminophen hepatotoxicity is associated with its biotransformation to the reactive metabolite N-acetyl-p-benzoquinone imine that binds to protein. Two forms of cytochrome P450, CYP2E1 and CYP1A2, have been implicated as primarily responsible for the bioactivation. To determine the relative contributions of these P450's, overnight fasted male NMRI mice were pretreated with 10 ml of 50% v/w propylene glycol/kg or fluvoxamine (10 mg/kg) at -80 and -20 min. relative to acetaminophen dosing to inhibit CYP2E1 and CYP1A2, respectively. Mice were sacrificed at 0.5 or 4 hr after a hepatotoxic dose of acetaminophen (300 mg/kg). Propylene glycol or propylene glycol plus fluvoxamine, but not fluvoxamine alone protected against acetaminophen hepatotoxicity as indicated by abolished increase in serum alanine aminotransferase activity, less depletion of hepatic glutathione and lower liver:body weight ratios. Propylene glycol inhibited the activity of CYP2E1 as indicated by 84% reduction in the clearance of 3 mg/kg dose of chlorzoxazone, whereas fluvoxamine inhibited the activity of CYP1A2 as indicated by 40% reduction in the clearance of a 10 mg/kg dose of caffeine. For this animal model, the data are consistent with the notion that hepatoxicity is associated with bioactivation of acetaminophen by CYP2E1 but not by CYP1A2.

Acetaminophen↗

PubMed1994

[The effect on health of dietary antioxidants and antioxidant supplements].

Reactive free oxygen radicals are formed in the reactions involved in normal cell metabolism. This formation is closely regulated e.g. by dietary antioxidants. Present knowledge suggests that an imbalance, with surplus of free radicals, can play a role in the pathogenesis of certain types of cancer, atherosclerosis, and cataract. A number of epidemiological studies have demonstrated a reduced risk of developing these diseases in persons who consume a diet with a high content of vegetables and fruit, which contains large quantities of the antioxidants: beta-carotene, vitamins C and E. Intervention studies, using supplements of these antioxidants, have so far not been able to show a beneficial effect. The apparently protective effect of fruit and vegetables may be due to other active ingredients. In Denmark the average intake of vegetables and fruit is low, and it is estimated that an increased consumption of these foods could reduce the occurrence of certain cancer types and atherosclerosis. In contrast, there is no evidence that antioxidant supplements would provide protection against disease, and their safety remains to be established.

Antioxidants↗

PubMed1994

Simultaneous determination of urinary free cortisol and 6 beta-hydroxycortisol by high-performance liquid chromatography to measure human CYP3A activity.

The ratio of the hydrophilic metabolite 6 beta-hydroxycortisol to its parent compound cortisol has recently been demonstrated to be a specific marker for human CYP3A oxygenase activity. We have developed a sensitive and simple single-run high-performance liquid chromatographic method for the quantification of urinary free cortisol and 6 beta-hydroxycortisol using dexamethasone as internal standard. The urine samples (1 ml) are applied to Sep-Pak cartridges, which are washed with water and eluted with ethyl acetate-diethyl ether (4:1, v/v). The organic extracts are washed sequentially with alkaline and acidic solutions saturated with sodium sulfate and subsequently concentrated to dryness. After reconstitution in ethanolic water, the samples are analyzed on a reversed-phase gradient system using ultraviolet absorbance detection at 254 nm. The within- and between-day coefficients of variation (C.V.) for the assay where both in the range of 5-10%. The reference interval for the 6 beta-hydroxycortisol/cortisol ratio of eleven healthy non-smoking subjects was 2.77-26.88 with an average of 10.09 +/- 6.89 (S.D.). The method constitutes an improvement over previous methods and is suitable for routine assessment of the 6 beta-hydroxycortisol/cortisol ratio requiring only 1 ml of urine or less.

Biomarkers↗

PubMed1992

Effects of cysteine and acetaminophen on the syntheses of glutathione and adenosine 3'-phosphate 5'-phosphosulfate in isolated rat hepatocytes.

The aim of the present study was to introduce and validate a radioactive tracer method in which adenosine 3'-phosphate 5'-phosphosulfate (PAPS) and glutathione (GSH) are measured simultaneously in isolated hepatocytes. PAPS and GSH are co-substrates in sulphation and GSH conjugation, and both are dependent on sulphur deriving from cysteine. The effect of cysteine on the syntheses was investigated at non-toxic and toxic concentrations of the hepatotoxic drug acetaminophen (AA). Administration of AA trapped radioactivity (35S) in the pre-labelled PAPS and GSH pools by formation of the metabolites, AA-sulphate and AA-GSH. Turnover rates were determined from the decline of AA-sulphate and AA-GSH specific activity. Syntheses of PAPS and GSH were calculated by multiplying the rates with the concentrations of the respective co-substrates. Increasing AA concentration from non-toxic to toxic levels resulted in increased median PAPS and GSH syntheses (8 to 11 and 311 to 2218 nmol/10(6) cells/min, respectively) (P less than 0.05). Addition of cysteine did not alter median PAPS synthesis (5 to 3 nmol/10(6) cells/min) but decreased median GSH synthesis (666 to 261 nmol/10(6) cells/min) (P less than 0.05) in experiments with non-toxic AA concentrations. In experiments with toxic AA concentrations opposite effects of cysteine were seen, i.e. median PAPS synthesis was reduced (3 to 2 nmol/10(6) cells/min) (P less than 0.05) while median GSH synthesis was unchanged (23 to 16 nmol/10(6) cells/min). The present method provides a tool in which two important detoxification pathways can be measured simultaneously and the data suggest that the two pathways are regulated by substrate availability.

Acetaminophen↗

PubMed1992

Influence of intact and myrosinase-treated indolyl glucosinolates on the metabolism in vivo of metronidazole and antipyrine in the rat.

Induction of the cytochrome P-450 enzymes is a mechanism whereby cruciferous vegetables and their glucosinolates could influence the risk of cancer. The cytochrome P-450-inducing capacity of isolated intact broccoli glucosinolates and their degradation products, resulting from myrosinase-catalysed hydrolysis, has been assessed in studies of the metabolism of antipyrine (AP) and metronidazole (MZ) in the rat. The intact glucosinolates had no effect on the metabolism of MZ and AP as measured by the clearance and metabolite formation rates; however, the myrosinase-treated glucosinolates significantly increased the clearance of AP by two-thirds and the formation rates of the three major AP metabolites by 87-100%, and doubled the rate of oxidative metabolism of MZ to its hydroxy and acetic acid metabolites. Active myrosinase was thus essential for the capacity of glucosinolates from broccoli (mainly indolyl glucosinolates) to induce the activity of several cytochrome P-450 isoenzymes involved in the metabolism of AP and MZ. The data indicated that hydrolysis products of indolyl glucosinolates had an inducing effect on the activity, but not the total amount, of hepatic cytochrome P-450 isoenzymes. The effect of these products on the oxidative metabolism of AP and MZ was similar to that of phenobarbital. The significance of this induction pattern in relation to cancer risk depends primarily on the activation/inactivation mechanism of the relevant carcinogen.

Animals↗

PubMed1992

8-Hydroxydeoxyguanosine in vitro: effects of glutathione, ascorbate, and 5-aminosalicylic acid.

Oxidative DNA damage, as expressed by 8-hydroxydeoxyguanosine (8-OHdG), was investigated in calf thymus DNA exposed to either ultraviolet radiation or to FeCl2/H2O2 in a Fenton-like reaction. The influence of iron (absent in the UV system and present in the FeCl2/H2O2 system) and pH (7.4 and 4.0) on the effect of glutathione (GSH), ascorbate, and 5-aminosalicylic acid (5-ASA, a drug used in the treatment of chronic inflammatory bowel diseases) was examined in these systems. Without iron, all three compounds considerably reduced 8-OHdG formation (i.e., acted as scavengers), while in the presence of iron salts, 8-OHdG formation was accelerated (except for GSH at pH 7.4), i.e., the compounds acted as prooxidants. This effect was augmented at low pH. The prooxidant property of 5-ASA may have implications for its clinical use. Maximum scavenging effect for all the compounds investigated was obtained at much lower doses than the maximum enhancing effect. This demonstrates that to the end of oxy-radical scavenging, the concentration of the GSH, ascorbate, and 5-ASA, respectively, should be chosen to obtain maximum antioxidant effect and minimum prooxidant effects. The significance of this finding for the selection of antioxidant dose is important but remains to be investigated further.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1992

Oxidative DNA damage estimated by 8-hydroxydeoxyguanosine excretion in humans: influence of smoking, gender and body mass index.

Oxidative DNA damage may be implicated in ageing, carcinogenesis and other degenerative diseases. Oxidative DNA damage can be assessed in humans in vivo from the urinary excretion of the DNA-repair product 8-hydroxydeoxyguanosine (8OHdG). We investigated factors influencing the excretion of 8OHdG in 24 h urine from 83 randomly selected healthy subjects (52 women) aged 40-64 years. For 2 weeks prior to urine collection the subjects kept a weighed diet record. 8OHdG was quantified by an automatic three-dimensional HPLC analysis with electrochemical detection. The 8OHdG excretion was 252 +/- 103 (mean +/- SD) pmol kg body weight/24 h with a range from 78 to 527. Multiple regression analysis identified three factors, smoking, body mass index (BMI) and gender, as significant predictors of the 8OHdG excretion. In 30 smokers the 8OHdG excretion was 320 +/- 99 pmol/kg/24 h opposed to 213 +/- 84 pmol/kg/24 h in 53 non-smokers. According to multiple regression analysis smokers excreted 50% (31-69%; 95% confidence interval) more 8OHdG than non-smokers. In 52 women the 8OHdG excretion was 240 +/- 106 pmol/kg/24 h opposed to 271 +/- 96 pmol/kg/24 h in 31 men. According to the multiple regression analysis men excreted 29% (10-48%) more 8OHdG than women. According to multiple regression analysis the 8OHdG excretion decreased with 4% (2-6%) per increment in BMI measured in kg/m2. The dietary distribution of energy demonstrated no important predictive value with respect to 8OHdG excretion. The intake of the antioxidant vitamins C and E and of vitamin A equivalents, including beta-carotene, was not associated with 8OHdG excretion. The results suggest that smoking increases oxidative DNA damage by approximately 50%. This effect implies potential serious health effects adding to the other well-known health hazards of smoking. The higher 8OHdG excretion in men and lean subjects may be related to a higher rate of metabolism with increased availability of reactive oxygen species. The apparent 7-fold individual variation in oxidative DNA damage carries implications regarding the rate of ageing and the risk of cancer and other degenerative diseases. The excretion of 8OHdG into urine offers a valuable tool for testing such hypotheses in humans.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1992

Foreign compound metabolism capacity in man measured from metabolites of dietary caffeine.

Caffeine is sequentially metabolized by cytochrome P4501A2 (CYP1A2), N-acetyltransferase (NAT) and/or xanthine oxidase (XO). In the present study the activity of these three enzymes was estimated from ratios of the metabolites formed from dietary caffeine and excreted into the urine collected as spot samples. In the urine samples from 10 out of 377 subjects concentrations of caffeine metabolites were too low to allow reliable measurements of the ratios. In 335 healthy subjects the NAT activity showed a typically bimodal distribution with 47% fast acetylators and 53% slow acetylators, consistent with a Danish population. The ratios reflecting CYP1A2 and XO activities were log normal and normal distributed, respectively. In 103 non-smoking men and 90 non-smoking women the ratio of caffeine metabolites expressing CYP1A2 activity was 4.7 +/- 1.6 and 4.3 +/- 1.9 as compared to 7.8 +/- 2.5 and 7.3 +/- 3.0 in 31 male and 25 female subjects smoking 10 cigarettes/day or more respectively, verifying induction of CYP1A2 by tobacco (P less than 0.05), but minimal sex-related differences. In 12 non-smoking pregnant women and in 28 women using oral contraceptives the CYP1A2 ratio was 29 and 20% reduced respectively (P less than 0.05). In a multivariate analysis the only significant predictor of the XO ratio was the consumption of caffeine with an increase of 2% per cup of coffee or equivalent (P less than 0.05). In 23 healthy male subjects 30 days of vigorous exercise increased the CYP1A2 ratio by 70% and the XO ratio by 42% (P less than 0.05), but left the NAT ratio unchanged. In nine healthy volunteers daily ingestion of 500 g of broccoli for 10 days increased the CYP1A2 ratio by an average of 12% (P less than 0.05), compared to a control period with ingestion of an equivalent weight of non-cruciferous green vegetables. The ratios of metabolites from dietary caffeine in spot urine samples offer ethical, non-invasive and reliable estimates of CYP1A2, NAT and XO. These enzymes are highly relevant for the bioactivation of potentially toxic compounds and the formation of oxygen radicals. The method is applicable in large-scale epidemiological studies, allowing, for example, prospective testing of the relationship between these enzyme activities and the development of disease. Exercise may increase CYP1A2 activity to a magnitude corresponding to heavy smoking, as well as XO by mechanisms that remain to be clarified.

Acetylation↗

PubMed1992

Glutathione treatment of hepatocellular carcinoma.

This prospective study was undertaken to substantiate observations that glutathione (GSH) inhibits or reverses tumor growth in humans with hepatocellular carcinoma (HCC), a neoplasm with an extremely poor prognosis. Eight patients with biopsy-proven HCC not amenable to surgery were given 5 g of GSH daily from the time of diagnosis. Two patients withdrew shortly after receiving GSH due to intolerable side-effects. Of the six eligible patients, two had mildly advanced tumors and four moderately advanced tumors. At 1-2-month intervals the liver was CT and ultra-sound scanned to assess the growth status of the tumor (progression, stagnation or regression). All the patients, except a male with a fibrolamellar type of HCC, died within 1 year after diagnosis. Two women with moderately advanced tumors survived almost 1 year, tumor growth stopped or regressed and in one of the women an initially abnormal alfa-1-fetoprotein (AFP) returned to normal after GSH treatment. AFP remained normal throughout the treatment period in the other women. These observations indicate that GSH may have a sex-dependent effect on HCC. However, further studies involving more patients are required to pursue this hypothesis.

Adult↗

PubMed1992

Interaction of smoking, uptake of polycyclic aromatic hydrocarbons, and cytochrome P450IA2 activity among foundry workers.

An increased lung cancer risk has been described among foundry workers. Polycyclic aromatic hydrocarbons (PAHs) and silica are possible aetiological factors. This study describes a urinary PAH metabolite, 1-hydroxypyrene (hpU), as well as the degree of cytochrome P450IA2 activity/induction as reflected by the urinary caffeine ratio (IA2) in 45 foundry workers and 52 controls; IA2 was defined as the ratio of paraxanthine 7-demethylation products to a paraxanthine 8-hydroxylation product (1,7-dimethyluric acid). Mean exposure concentrations for foundry workers were defined by breathing zone hygienic samples (respirable dust 1.2 to 3.52 mg/m3 (93 samples)) and as total PAH (0.46 micrograms/m3) and pyrene concentrations (0.28 micrograms/m3) (six samples). Non-smoking controls and foundry workers had similar IA2 ratios (5.63, 95% confidence interval (95% CI) 4.56-6.70 and 4.40, 95% CI 3.56-5.24). The same was true for smoking controls and foundry workers (9.10, 95% CI 8.00-10.20 and 8.69, 95% CI 7.37-10.01). Both smoking groups had raised IA2 ratios compared with non-smokers (p less than 0.01). Non-smoking controls and foundry workers had similar hpU concentrations (0.16, 95% CI 0.10-0.22 and 0.11, 95% CI 0.09-0.13 mumol/mol creatinine). Smoking foundry workers had raised hpU concentrations (0.42, 95% CI 0.25-0.59) compared with smoking controls (0.26, 95% CI 0.18-0.34) (p less than 0.01). A small subgroup of smoking foundry workers with the highest exposures to both silica and PAH also had the highest hpU concentrations (0.70, 95% CI - 0.07-1.47 mumol/mol creatinine) (p less than 0.04). Increased hpU concentrations in smoking foundry workers suggest a more than additive effect from smoking and foundry exposures resulting in increased PAH uptake. Increased P450IA2 enzyme activity was only found in smokers and no additional effect of foundry exposures was seen. These data suggest that smoking as well as work related PAH exposure may be casually related to increased risk of lung cancer in foundry workers.

Adult↗