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Archives of Toxicology (v.71, #8)

Sulphation of the heterocyclic amine 1,2,3,4-tetrahydroisoquinoline in the human liver and intestinal mucosa: interindividual variability by G. M. Pacifici; C. D'alessandro; A. Gucci; L. Giuliani (pp. 477-481).

The sulphation rate of 1,2,3,4-tetrahydroisoquinoline (TIQ) was measured in the human liver and in the intestinal mucosa isolated from the transverse colon, ileum and duodenum. The rate (mean ± SD) of hepatic TIQ sulphation was 500 ± 174 pmol/min per mg in women (n=61) and 591 ± 201 in men (n=39; P=0.0087), varying over one order of magnitude in men and women. The sulphation rate of testosterone showed the same sex-dependent pattern and was correlated (r=0.6055; P<0.001) with that of TIQ. The frequency distribution of TIQ sulphation rate in human liver was bimodal: 70% of the population fell into the low-activity subgroup and the remaining 30% feel into the high-activity subgroup. In the colon (n=56), the rate of TIQ sulphation was 30.4 ± 15.6 pmol/min per mg and the values were similar in men and women (29.8 and 30.9 pmol/min per mg, respectively) but, varied over one order of magnitude and correlated (r=0.7231; P<0.001) with that of 4-nitrophenol. The rate of TIQ sulphation changed along the human bowel and mean (±SD) estimates for duodenum, ileum and transverse colon were 444 ± 25, 182 ± 87 and 30.4 ± 15.6 pmol/min per mg, respectively. The present results are consistent with the view that the heterocyclic amine TIQ is sulphated in the human liver and intestinal mucosa. TIQ-sulphotransferase activity varies among subjects and is mostly associated with the liver and duodenum.

Keywords: Key words Sulphotransferase; Liver; Intestine; Man; Variability

The GST T1 and CYP2E1 genotypes are possible factors causing vinyl chloride induced abnormal liver function by Chung-Ying Huang; Kuo-Liang Huang; Tsun-Jen Cheng; Jung-Der Wang; Ling-Ling Hsieh (pp. 482-488).

Vinyl chloride monomer (VCM) is hepatotoxic as well as carcinogenic in humans. There are reports that exposure to VCM seems to induce abnormal liver function, liver fibrosis, cirrhosis, portal hypertension, and angiosarcoma of the liver. In vivo, VCM is metabolized by cytochrome P450 2E1 (CYP2E1) to form the electrophilic metabolites, chloroethylene oxide (CEO) and chloroacetaldehyde (CAA), which may either cause cell damage or be further metabolized and detoxified by glutathione S-transferases (GSTs). This study investigated whether or not the genotypes CYP2E1, glutathione S-transferase θ (GST T1) and μ (GST M1) correlated with abnormal liver function found in vinyl chloride exposed workers. For this study, 251 workers from five polyvinyl chloride plants were enrolled. The workers were classified into two exposure groups (high and low) and the degree of exposure was determined based on their job titles and airborne VCM concentration. The activity of serum alanine aminotransferase (ALT) was used as the parameter of liver function. The genotypes CYP2E1, GST T1 and GST M1 were determined by polymerase chain reaction and restriction fragment length polymorphism on peripheral white blood cell DNA. Other potential risk factors were also ascertained and the confounding effect was adjusted accordingly. Stratified analyses were used to explore the correlation between the alteration of liver function and the genotypes CYP2E1, GST T1 and GST M1 among the workers exposed to different levels of VCM. The following results were obtained (1) at low VCM exposure, the odds ratio (OR) of positive GST T1 on abnormal ALT was 3.8 (95% CI 1.2–14.5) but the CYP2E1 genotype was not associated with abnormal ALT. (2) At high VCM exposure, a c2c2 CYP2E1 genotype was associated with increased OR on abnormal ALT (OR 5.4, 95% CI 0.7–35.1) and positive GST T1 was significantly associated with decreased OR on abnormal ALT (OR 0.3, 95% CI 0.1–0.9). (3) Multiple linear and logistic regression also showed strong interactions of the VCM exposure to CYP2E1 as well as to the GST T1 genotype. These observations suggest that the two genotypes, CYP2E1 and GST T1, may play important roles in the biotransformation of VCM, the effect of which leads to liver damage.

Keywords: Key words Vinyl chloride; Glutathione S-transferases; Cytochrome P-450 2E1; Liver function

Induction of cytochromes P450 1A, 2B and 2E in hamster tissues by acetone by Ruei-Ming Chen; Tzuu-Huei Ueng (pp. 489-495).

The inductive effects of acetone on cytochromes P450 1A, 2B and 2E in liver, kidney and lung were studied using hamsters administered acetone in drinking water. Acetone administration caused five-, two- and sixfold increases of the activities of aniline hydroxylase, ethoxyresorufin O-dealkylase and pentoxyresorufin O-dealkylase in liver microsomes; eight- and twofold increases of aniline hydroxylation and ethoxyresorufin O-dealkylation in kidney; and a twofold increase of aniline hydroxylation in lung, respectively. Immunoblot analyses of microsomal proteins using mouse monoclonal antibody 1-12-3 to rat P450 1A1 and rabbit antibody to human P450 2E1 revealed that acetone resulted in about three-, four- and twofold increases of proteins immunorelated to P450s 1A and 2E in hamster liver, kidney, and lung, respectively. Protein blot analysis using mouse monoclonal antibody 2-66-3 to rat P450 2B1 showed that acetone caused five- and twofold increases, respectively, of an immunoreactive protein in hamster liver and kidney but decreased the P450 2B protein by 48% in lung. RNA blot analyses using cDNA probes derived from mouse P450 1A1 and rat P450 2B1 cDNA clones demonstrated that acetone elicited two- and twelvefold increases of the mRNA levels of P450s 1A and 2B in hamster liver, respectively. Northern blot analyses using oligonucleotide probes derived from hamster P450 2E1 cDNA sequence detected two species of hybridizable mRNA in control liver. Acetone preferentially caused a threefold increase in the level of the larger-sized mRNA. Acetone produced little increase or no effect on mRNAs of cytochromes P450 1A, 2B and 2E in kidney and lung. The present study demonstrates that acetone induces the catalytic activity, protein and mRNA levels of P450s 1A, 2B and 2E in hamster liver, and causes various changes of the P450 levels in kidney and lung. Acetone induction of hamster P450s 1A, 2B and 2E might involve transcriptional and post-transcriptional mechanisms.

Keywords: Key words Acetone; Cytochrome P450; Induction; Hamster

Detection of 8-hydroxydeoxyguanosine, a marker of oxidative DNA damage, in white blood cells of workers occupationally exposed to styrene by B. Marczynski; P. Rozynek; H.-J. Elliehausen; M. Korn; X. Baur (pp. 496-500).

Styrene-7,8-oxide (SO), the major in vivo metabolite of styrene, is a genotoxic compound and a potential carcinogenic hazard to occupationally exposed workers. The aim of the present work was to investigate the ability of styrene exposure to induce formation of 8-hydroxy-2′-deoxyguanosine (8-OHdG) in white blood cells (WBC) of boatbuilders occupationally exposed to styrene. The study of these adducts was conducted to see if styrene exposure can cause oxidative damage of DNA. The 8-OHdG/10⁵ dG ratio from 17 styrene-exposed workers showed significant increases (mean ± SD, 2.23 ± 0.54, median 2.35, P < 0.001) in comparison to the controls (1.52 ± 0.45, median 1.50). However, 11 out of 17 workers who were between the ages of 32 and 60 years and had been occupationally exposed to styrene for >10 years showed higher 8-OHdG/10⁵ dG ratios (2.31 ± 0.62, median 2.37) in comparison to 6 workers with <6 years of occupational styrene-exposure (2.11 ± 0.36, median 2.05; P > 0.05, no significant difference between the two groups of workers). The studies presented here provide an indication that styrene exposure can result in oxidative DNA damage.

Keywords: Key words Styrene; Styrene-7; 8-oxide; Human white blood cells; 8-Hydroxy-2′-deoxyguanosine; Oxidative DNA damage

Using a four-compartment closed model to describe inhalation of vaporised ethanol on 1-14C-pyruvate kinetics in mice by Guang Wu (pp. 501-507).

A four-compartment closed model was set up by means of a system of differential equations. A completely analytical solution of the four-compartment closed model was found by means of Laplace transform and Cramer's rule. 1-¹⁴C-pyruvate kinetics were studied in mice without and with inhalation of vaporised ethanol. The 1-¹⁴C-pyruvate kinetics were modelled by the four-compartment closed model, i.e. injected site, blood, ¹⁴CO₂ expired in air, and ¹⁴C eliminated in urine. The kinetic parameters were estimated using the analytical solution of the four-compartment closed model to fit expired ¹⁴CO₂ and ¹⁴C eliminated in urine simultaneously. Although the results showed that the inhalation of vaporised ethanol increased the expired ¹⁴CO₂, the␣compartmental analysis revealed that the increase of␣expired ¹⁴CO₂ is mainly attributed to increased 1-¹⁴C-pyruvate transmembrane process. The developed model is useful for toxicokinetic analysis when blood is not easy to obtain. Moreover, the developed model can also be used to model two compartments as urine and faeces when the toxin is not eliminated through air.

Keywords: Key wordsAnalytical solution; Compartmental model; Kinetics; Pyruvate; Vaporised ethanol

Thyroid peroxidase as toxicity target for dithiocarbamates by M. Marinovich; M. Guizzetti; F. Ghilardi; B. Viviani; E. Corsini; C. L. Galli (pp. 508-512).

In vivo ethylenebisdithiocarbamates and ETU are toxic to the thyroid gland. Since the molecular target of these compounds is thought to be thyroid peroxidase (TPO) which catalyzes the transfer of iodine to thyroglobulin, we examined the effect of these compounds on peroxidative activity in Chinese hamster ovary (CHO) cells transfected with the human TPO gene. The activity was inhibited by 50 μM ETU, 5 μM ziram and 5 μM zineb, the last-mentioned effect being irreversible in the absence of iodide. Thiram had no effect. By contrast, the iodinating activity of TPO was blocked only by 5 μM ETU and 50 μM zineb but not by the other compounds. The effect on TPO-catalysed iodination could explain the differences in thyrotoxicity of these compounds in vivo.

Keywords: Key words Dithiocarbamates; Thyroid peroxidase; Ethylenethiourea

Effect of SKF-525A on liver metabolism and hepatotoxicity of tri- and dibutyltin compounds in mice by Shunji Ueno; Takashi Suzuki; Nobuyuki Susa; Yoshinori Furukawa; Masayasu Sugiyama (pp. 513-518).

The effect of pretreatment with SKF-525A, which inhibits hepatic cytochrome P450 enzymes, on metabolism and hepatotoxicity was examined in mice orally administered tributyltin chloride (TBTC) or dibutyltin dichloride (DBTC) at a dose of 180 μmol/kg. Analysis of butyltin compounds showed that the main metabolites in liver of mice treated with TBTC alone were DBTC (40%) and dibutyl(3-carboxylpropyl)tin chloride (TCOOH; 12–26%), with the levels of other butyltin compounds including TBTC comprising <12% of total butyltin compounds at 3–24 h following treatment. The pretreatment with SKF-525A resulted in four- to tenfold increased TBTC levels and a significant decrease of debutylated metabolites, particularly DBTC (60 and 37% decrease) at both 3 and 6 h in liver of mice treated with TBTC, leading to complete inhibition of hepatotoxicity at 24 h. At 24 h after TBTC treatment, hepatic levels of TBTC and most of the debutylated metabolites in mice pretreated with SKF-525A did not differ significantly when compared to those in unpretreated mice, resulting in the induction of hepatotoxicity at 48 h, although levels of TCOOH decreased even at 24 h. In the case of DBTC treatment, >95% of the butyltin compounds were detected as DBTC in liver, and the levels of DBTC inside cells as well as the induction of DBTC hepatotoxicity were unaffected by pretreatment with SKF-525A. These results suggest that debutylated metabolites, in particular DBTC, are the main metabolites of butyltin compounds responsible for the induction of hepatotoxicity following in vivo administration of TBTC. The results also indicate that cytochrome P450 enzymes may play a greater role in the metabolism of TBTC to form DBTC or butyltin trichloride (MBTC) than that of DBTC to form MBTC in liver of mice.

Keywords: Key words Butyltin compounds; Hepatotoxicity; Cytochrome P450

The effects of lithium on neurulation stage mouse embryos by James J. Giles; John G. Bannigan (pp. 519-528).

The aim of this study was to evaluate the maternal toxicity and teratogenicity of lithium following intraperitoneal injection (i.p.) with lithium carbonate (Li₂CO₃) in pregnant CD-1 mice at the developmental stage of neurulation (E8; day of vaginal plug, E0). Light (LM) and electron (TEM) microscopic studies were also done to document the tissue and cellular changes occurring in embryonic tissues during the 48 h following treatment with 300 mg/kg body wt. Li₂CO₃. Controls were untreated or given equimolar amounts of NaCl or Na₂CO₃. A pharmacokinetic study showed that lithium was rapidly absorbed from the peritoneal cavity after the above-stated dose, achieved peak serum levels of 9.8 mmol/l within 1 h, had a half-life in the blood of 5 h and was completely cleared by 16 to 24 h after injection. Doses of Li₂CO₃>300 mg/kg body wt. were toxic to adult CD-1 mice. The latter dose had no detectable maternal toxicity but caused a 19% resorption rate and 2% incidence of open cranial neural tube defect in gestations terminated on E18. The malformation and resorption rates in gestations terminated on E11, E12 and E14 were not significantly different from those of E18. A strong litter effect was seen both for the resorption and malformation rates at all stages examined. At 3 h after treatment cell death became evident in the neuroepithelium. Cells continued to die for ∼17 h and all necrotic debris had been cleared by 48 h. Also at 3 h after treatment small densely stained inclusions began to appear in mesodermal cells. TEM showed these to be non-membrane bound with an irregular shape and variable size; the lack of staining for acid phosphatase indicated a non-lysosomal structure; the ultrastructural features suggested a lipoid basis. At 24 h after treatment vascular ruptures and surface ectodermal ruptures were seen in the cranial mesoderm. These ruptures with extravascated blood were also seen at 48 h after treatment. A litter effect was also noted with respect to the tissue and cellular changes. These experiments suggest that the developing vascular system may be a target for lithium. In addition, the possibility is discussed that lithium induced cell death in the neuroepithelium may lead to neural tube defects.

Keywords: Key words Lithium; Teratology; Neuroepithelium Vasculature

Modulation of energy status and cytotoxicity induced by FK506 and cyclosporin A in a renal epithelial cell line by France Massicot; Chantal Martin; Hélène Dutertre-Catella; Sophie Ellouk-Achard; Chuong Pham-Huy; Marc Thevenin; Pierre Rucay; Jean-Michel Warnet; Jean-Roger Claude (pp. 529-531).

FK506 and cyclosporin A (CsA) are two potent immunosupressants with similar toxicity profile. Nephrotoxicity is the main adverse effect of both compounds. The aim of this study is to compare the in vitro nephrotoxic effects on renal epithelial cell line LLC-PK1 by measuring cell viability and energy status as evaluated by concentrations of ATP and ATP metabolites. Cell viability (expressed as IC₅₀ was assessed via thiazolyl blue (MTT) assay after incubation for 4–24 h with FK506 or CsA. ATP and its metabolites were determined by HPLC after 4 and 6 h incubation with FK506 or CsA alone at the respective IC₅₀. Both FK506 and CsA decreased cell viability to similar extents, in a dose- and time-dependent manner. After 4 h incubation, both drugs decreased ATP levels (−25%) and increased uric acid levels. However, the latter percentage increase was twofold higher with CsA (18%) than with FK506 (9%). The energy charge, calculated according to levels of adenine nucleotides, was decreased by 10% in FK506-treated cells and by 27% in CsA-treated cells. At the end of 6-h incubation, FK506-treated cells maintained ATP levels coupled with energy charge at near control levels whereas the levels were 32% lower in CsA treated cells. Compared to the 4 h-incubation, the increase in uric acid was similar for FK506 but was doubled with CsA. The decrease in cell integrity and ATP depletion induced by CsA in LLC-PK1 cells was only transiently observed with FK506. By preserving energy status, FK506 leads to fewer metabolic disturbances than CsA in the renal epithelial cell line LLC-PK1, demonstrating a minor potential nephrotoxicity.

Keywords: Key words Nephrotoxicity; LLC-PK1 cells; FK506; Cyclosporin A; ATP

Biological durability and oxidative potential of a stonewool mineral fibre compared to crocidolite asbestos fibres by S. Hippeli; K. Dornisch; S. Kaiser; U. Dräger; E. F. Elstner (pp. 532-535).

Experiments are described concerning the differences in redox properties and biodurability of natural asbestos fibres and an experimental stonewool fibre incubated in Gamble solution and reconstructed surfactant fluid. Crocidolite exhibits a significantly higher oxidative potential compared to the tested stonewool fibres. The oxidative acitivity of both types of fibres is not constant during incubation over several weeks, but rather shows a sinoidal curve including reactivities much higher than those at the beginning of the incubation. A continuous loss of mass is concluded not to be definitively connected with a continuous loss of toxicity.

Keywords: Key words Asbestos fibres; Man-made vitreous fibres; Biodurability; Oxidative potential

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Archives of Toxicology (v.71, #8)