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Archives of Toxicology (v.78, #8)

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 by Wei Chao Guo; Guo Fang Lin; Ji Gang Chen; Klaus Golka; Jian Hua Shen (pp. 425-429).

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 T₁₀₈₈A. A nested PCR-RFLP procedure was conducted to differentiate NAT1*14A (T₁₀₈₈A, C₁₀₉₅A, and G₅₆₀A) from NAT1*10 (T₁₀₈₈A, C₁₀₉₅A). No significantly different frequencies of homozygous and heterozygous NAT1*10 alleles were found among the subgroups with (i) gradings according to Papanicolaou ≤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.

Keywords: Aromatic amines; Dyes; N-Acetyltransferase 1; Papanicolaou’s test; Polymorphism; Transitional cell carcinoma

Polymorphism of GSTM1 and GSTT1 genes in bladder cancer: a study from North India by Daya Shankar Lal Srivastava; Anant Kumar; Balraj Mittal; Rama Devi Mittal (pp. 430-434).

The present study was conducted (1) to examine whether the GSTT1- and GSTM1-null genotypes are risk factors for bladder cancer, and (2) to study possible association of tobacco usage and age strata with genotype of these patients. This case control study was undertaken over a period of 19 months and included 106 bladder cancer patients and 182 controls; both patients and controls originated from northern part of India. The GSTT1 and GSTM1 genotypes were identified by multiplex PCR in peripheral blood DNA samples. Genotype frequencies among patients and controls were assessed and the association of the genotypes with smoking habits and gender of the patients were statistically determined by the χ² test. Frequencies of null genotypes in GSTT1 and GSTM1, were 16% (29/182) and 30% (54/182), respectively, in control individuals. The frequencies of GSTT1- and GSTM1-null genotypes in bladder cancer patients were 26% (28/106) and 40% (42/106), respectively. In conclusion, our study demonstrated that the null genotypes of GSTT1 and GSTM1 were substantially at higher risk for bladder carcinoma compared to the normal healthy controls. The GSTT1- and GSTM1-null genotypes did not show significant association with tobacco usage in bladder cancer patients. However, the null genotypes were statistically significant in female relative to male bladder cancer patients.

Keywords: Bladder cancer; Glutathione S-transferase; Genetic polymorphism; Null genotype; Multiplex PCR

Molecular mechanism investigation of phenobarbital-induced serum cholesterol elevation in rat livers by microarray analysis by Naoki Kiyosawa; Kohji Tanaka; Jun Hirao; Kazumi Ito; Noriyo Niino; Kyoko Sakuma; Miyuki Kanbori; Takashi Yamoto; Sunao Manabe; Naochika Matsunuma (pp. 435-442).

Phenobarbital (PB) increases serum total cholesterol levels in rodents and humans. To investigate the underlying molecular mechanisms, we performed a microarray analysis on liver of rats treated repeatedly with 100 mg/kg PB, and examined the serum blood chemistry. The serum concentration of non-esterified fatty acids was decreased from day 1 to day 14 except for day 7, and that of cholesterol was increased from day 4 to day 14. The serum concentration of total ketone bodies was increased on day 7, and that of triglycerides was decreased on day 14. Transcript content of glycolytic genes was decreased by PB treatments, while that of lipoprotein lipase was continuously increased, suggesting a notion that repetitive PB treatments impaired glycolysis and stimulated lipolysis in the liver. The hypothesis was examined by using a previously reported flux-balance model. The increase in mRNA content of malic enzyme after the PB treatment agreed well with the flux-balance model result, suggesting the validity of our hypothesis. The findings also suggested that there was an abundance of acetyl-CoA and shortage of glycolytic products after the repeated PB treatments. Although ketogenesis would normally occur under such cellular conditions, it was only weakly observed after the repeated PB treatments, presumably owing to a decrease in HMG-CoA synthase mRNA content. On the other hand, the mRNA content of several cholesterogenic genes was slightly induced by PB treatments. Thus, serum chemistry and microarray results suggested that repeated PB treatments induced cholesterogenesis in rat livers, which may have contributed to the elevation of the serum total cholesterol concentration.

Keywords: Phenobarbital; Microarray; Cholesterol; Ketone body; Metabolism

The effect of oxygen tension on the cytotoxicity of hydroquinone and selected hydroquinone metabolites to isolated rat renal proximal tubular cells by Rodney J. Boatman; J. Caroline English; Tammie S. Guerin; Linda M. Cummings (pp. 443-452).

The cytotoxicity of hydroquinone (HQ) and several of its metabolites was studied using freshly isolated proximal tubular (PT) kidney cells from rats. Incubations were conducted for periods of up to 4 h at 37°C, with cytotoxicity measured either as increased leakage of lactate dehydrogenase or as a decreased energy status, as determined by decreased ratios of adenosine triphosphate (ATP) to adenosine diphosphate (ADP). Incubation atmospheres consisted of either 95% O₂/5% CO₂, to promote cell viability in vitro, or 5% O₂/5% CO₂/90% N₂. Preliminary studies with bovine serum albumin (BSA) added to the incubation media indicated a lack of toxicity for HQ or its metabolites. For the tests discussed in this report, incubations were performed without the addition of BSA. Under 95% O₂ atmospheres, PT cells from male Fischer F344 rats were significantly more sensitive to HQ than those from male Sprague-Dawley (SD) rats, with decreases in ATP to ADP ratios seen as early as 0.5 h at a concentration of 0.5 mM. When incubations were performed under a 5% O₂ atmosphere, 2-(cysteine-S-yl)hydroquinone (Cys-HQ) and HQ toxicities were observed later (3–4 h) in the incubation period, occurred at higher concentrations, were similar in magnitude for the two strains, and were greater for Cys-HQ than for HQ. These results show that variations in oxygen tension can dramatically influence the toxicity of HQ and its metabolites. The specific compounds tested that were cytotoxic at a physiologically relevant oxygen tension (5%) were (in decreasing order of potency): Cys-HQ>2-(glutathion-S-yl)hydroquinone>HQ. These results support an association of toxicity with metabolism through the glutathione pathway, with ultimate toxicity associated with the cysteinyl conjugate. Biochemical characteristics of PT cells from these two strains suggest a significantly greater capacity of cells from the SD rat to respond to oxidative stress.

Keywords: Cytotoxicity; Hydroquinone; Metabolites; Rat; Renal proximal tubular cells

Effect of the antidepressant maprotiline on calcium movement and the viability of renal tubular cells by Shu-Shong Hsu; Wei-Chung Chen; Bang-Ping Jiann; Jin-Shyr Chen; Jong-Khing Huang; Hong-Tai Chang; He-Hsiung Cheng; Yuk-Keung Lo; Chin-Man Ho; Chung-Ren Jan (pp. 453-459).

In Madin-Darby canine kidney (MDCK) cells, the effect of maprotiline, an antidepressant, on intracellular Ca²⁺ concentration ([Ca²⁺]_i) was measured using fura-2. Maprotiline (>2.5 µM) caused a rapid rise of [Ca²⁺]_i in a concentration-dependent manner (EC₅₀ 200 µM). Maprotiline-induced [Ca²⁺]_i rise was reduced by removal of extracellular Ca²⁺ or by addition of La³⁺, but was not altered by voltage-gated Ca²⁺-channel blockers. Maprotiline-induced Mn²⁺ influx-associated fura-2 fluorescence quench directly suggests that maprotiline caused Ca²⁺ influx. In Ca²⁺-free medium, thapsigargin, an inhibitor of the endoplasmic reticulum Ca²⁺-ATPase, caused a monophasic [Ca²⁺]_i rise, after which the increasing effect of maprotiline on [Ca²⁺]_i was nearly abolished; also, pretreatment with maprotiline reduced a portion of thapsigargin-induced [Ca²⁺]_i rise. U73122, an inhibitor of phospholipase C, abolished [Ca²⁺]_i rise induced by ATP (but not by maprotiline). Overnight incubation with 1–10 µM maprotiline enhanced cell viability, but 20–50 µM maprotiline decreased it. These findings suggest that maprotiline rapidly increases [Ca²⁺]_i in renal tubular cells by stimulating both extracellular Ca²⁺ influx and intracellular Ca²⁺ release, and may modulate cell proliferation in a concentration-dependent manner.

Keywords: Ca²⁺ stores; Fura-2; Maprotiline; MDCK cells; Renal tubular cells

Inhibitory effects of KAT-681, a liver-selective thyromimetic, on development of hepatocellular proliferative lesions in rats induced by 2-acetylaminofluorene and partial hepatectomy after diethylnitrosamine initiation by Morimichi Hayashi; Hideki Ohnota; Toru Tamura; Junji Kuroda; Nobuo Shibata; Masuo Akahane; Hisataka Moriwaki; Noboru Machida; Kunitoshi Mitsumori (pp. 460-466).

To examine the potential inhibitory effects of a novel liver-selective thyromimetic, KAT-681 (KAT), on the development of hepatocellular proliferative lesions, male F344 rats were given a single intraperitoneal injection of 150 mg/kg diethylnitrosamine (DEN), followed by gavage administration of 7.5 mg/kg per day of 2-acetylaminofluorene (2-AAF) twice daily from weeks 2 to 4 with partial hepatectomy (PH) at week 3. From 5 weeks after the completion of 2-AAF administration, the rats were orally dosed with 0.04, 0.1, or 0.25 mg/kg per day KAT for 3 weeks, and subjected to morphometric analysis of the induced glutathione S-transferase placental form (GST-P)-positive lesions and hepatocellular adenomas (HCAs). Administration of KAT significantly and dose-dependently reduced the total area of GST-P-positive lesions (by 34–48%) and also their numbers (by 20–44%), their mean size not being significantly changed. No effects on the number of HCAs were apparent, although a reduction in their mean size was detected at a dose of 0.25 mg/kg per day KAT (by 34%). On biochemical analysis, serum activity of γ-glutamyl transpeptidase, an enzyme related to hepatocarcinogenesis, was markedly reduced in rats given 0.25 mg/kg per day KAT (by 64%). The results of the present study thus suggest that KAT inhibits the development of altered hepatocellular foci and might be a promising chemopreventive agent for hepatocarcinogenesis.

Keywords: Chemoprevention; Liver carcinogenesis; Thyromimetic; Thyroid hormone; Rat

Maternal exposure to nicotine and chlorpyrifos, alone and in combination, leads to persistently elevated expression of glial fibrillary acidic protein in the cerebellum of the offspring in late puberty by Ali Abdel-Rahman; Anjelika M. Dechkovskaia; Heena Mehta-Simmons; Jazmine M. Sutton; Xiangrong Guan; Wasiuddin A. Khan; Mohamed B. Abou-Donia (pp. 467-476).

We previously showed that maternal exposure to nicotine, alone or in combination with chlorpyrifos, caused an increase in glial fibrillary acidic protein (GFAP) immunostaining in the CA1 subfield of hippocampus and cerebellum in postnatal day (PND) 30 offspring. In the present study, PND 60 offspring were evaluated for histopathological and cholinergic effects following maternal exposure to nicotine and chlorpyrifos, alone and in combination. Timed-pregnant Sprague-Dawley rats (300–350 g) were treated daily with nicotine (1 mg/kg, s.c., in normal saline) or chlorpyrifos (0.1 mg/kg, dermal, in ethanol) or a combination of nicotine and chlorpyrifos from gestational days (GD) 4 to 20. Control animals were treated with saline and ethanol. On PND 60, the offspring were evaluated for cholinergic changes and pathological effects. Plasma butyrylcholinesterase (BChE) activity in the female offspring from chlorpyrifos treated mothers showed a significant increase (~183% of control). Male offspring from mothers treated with either chlorpyrifos or nicotine alone showed a significant increase in the acetylcholinesterase (AChE) activity in the brainstem while female offspring from mothers treated with either nicotine or a combination of nicotine and chlorpyrifos showed a significant increase (~134 and 126% of control, respectively) in AChE activity in the brainstem. No significant changes were observed in the ligand binding densities for α4β2 and α7 nicotinic acetylcholine receptors in the cortex. Histopathological evaluation using cresyl violet staining showed a significant decrease in surviving Purkinje neurons in the cerebellum of the offspring from nicotine treated mothers. An increase in GFAP immunostaining in cerebellar white matter was observed in the offspring from the mothers treated with nicotine. These results suggest that maternal exposure to real-life levels of nicotine and/or chlorpyrifos causes differential regulation of brainstem AChE activity. Also, nicotine caused a decrease in the surviving neurons and an increased expression of GFAP in cerebellar white matter of the offspring on PND 60. These changes can lead to long-term neurological adverse health effects later in life.

Keywords: Acetylcholinesterase; Cerebellum; Brainstem; Chlorpyrifos; Co-exposure; Gestational; Glial fibrillary acidic protein; Maternal; Neurotoxicity; Nicotine; Nicotinic acetylcholine receptor; Smoking

Short-term black tea intake modulates the excretion of urinary mutagens in rats treated with 2-amino-3-methylimidazo-[4,5-f]quinoline (IQ): role of CYP1A2 upregulation by V. R. Yoxall; D. A. Parker; P. A. Kentish; C. Ioannides (pp. 477-482).

Rats were exposed to black tea (2.5% w/v) as their sole drinking liquid for either 1 day or 1 month, while controls were maintained on water. After this treatment period, all animals received a single oral dose IQ (2-amino-3-methylimidazo-[4,5-f]quinoline), and urine was collected for 48 h. Mutagenic activity of the urine was determined in the Ames test in the presence and absence of an activation system. The excretion of direct-acting mutagens was markedly reduced following tea intake, and was more pronounced after the 1-day treatment. Similarly, both tea treatments suppressed the excretion of indirect-acting mutagens. Furthermore, both tea treatments induced hepatic CYP1A2 activity and expression, but cytosolic glutathione S-transferase activity was only modestly induced in the group of animals receiving tea for 1 day, and only when DCNB (1,2-dichloro-4-nitrobenzene) was used as substrate; glucuronosyl activity was elevated modestly only in the animals receiving the tea for a month. It is concluded that even short-term exposure to black tea is capable of influencing the metabolic fate of IQ, and this is most likely related to the upregulation of CYP1A2.

Keywords: Tea; 2-Amino-3-methylimidazo-[4,5-f]quinoline (IQ); Cytochrome P450; CYP1A2; Anticarcinogens; Heterocyclic amines

Developmental toxicity of polychlorinated biphenyls (PCBs): a systematic review of experimental data by Beate Ulbrich; Ralf Stahlmann (pp. 483-487).

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Archives of Toxicology (v.78, #8)