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Archives of Toxicology (v.82, #5)
Oxidative stress: from modification of cell-cycle related events, secondary messenger function, dysregulation of small GTPases, protein kinases and phosphatases to redox-sensitive cancer models
by J. G. Hengstler; H. M. Bolt (pp. 271-272).
Intracellular redox status and oxidative stress: implications for cell proliferation, apoptosis, and carcinogenesis by José M. Matés; Juan A. Segura; Francisco J. Alonso; Javier Márquez (pp. 273-299).
Oxidative stress can be defined as the imbalance between cellular oxidant species production and antioxidant capability. Reactive oxygen species (ROS) are involved in a variety of different cellular processes ranging from apoptosis and necrosis to cell proliferation and carcinogenesis. In fact, molecular events, such as induction of cell proliferation, decreased apoptosis, and oxidative DNA damage have been proposed to be critically involved in carcinogenesis. Carcinogenicity and aging are characterized by a set of complex endpoints, which appear as a series of molecular reactions. ROS can modify many intracellular signaling pathways including protein phosphatases, protein kinases, and transcription factors, suggesting that the majority of the effects of ROS are through their actions on signaling pathways rather than via non-specific damage of macromolecules; however, exact mechanisms by which redox status induces cells to proliferate or to die, and how oxidative stress can lead to processes evoking tumor formation are still under investigation.
Keywords: Apoptosis; Cancer; Glutamine; p53; Protein kinases; ROS
Uterotrophic assay, Hershberger assay, and subacute oral toxicity study of 4,4′-butylidenebis(2-tert-butyl-5-methylphenol) and 3-(dibutylamino)phenol, based on the OECD draft protocols by Kanji Yamasaki; Katusi Miyata; Keiji Shiraishi; Takako Muroi; Nobuhiko Higashihara; Hiroshi Oshima; Yasushi Minobe (pp. 301-311).
We performed a uterotrophic assay, the Hershberger assay, and a 28-day repeated-dose toxicity study [enhanced Organization for Economic Co-operation and Development (OECD) test guideline No. 407] of 4,4′-butylidenebis(2-tert-butyl-5-methylphenol) and 3-(dibutylamino)phenol, based on the OECD draft protocols. In the uterotrophic assay of 4,4′-butylidenebis(2-tert-butyl-5-methylphenol), female SD rats were subcutaneously injected with the chemical at doses of 0, 100, 300, and 1,000 mg/kg on each of 3 days from postnatal day 20 to day 22, and no changes were observed. In the Hershberger assay of 4,4′-butylidenebis(2-tert-butyl-5-methylphenol), the test chemical was orally administered to castrated male SD rats at doses of 0, 50, 200, and 1,000 mg/kg/day for ten consecutive days beginning on postnatal day 56, and no changes were observed. When this chemical was orally administered at doses 0, 5, 25, and 125 mg/kg/day for at least 28 days in the subacute oral toxicity study, an increase in thyroid weight was observed in the female rats in the 125 mg/kg group, an increase in serum thyroid-stimulating hormone (TSH) values in the male and female rats in the 125 mg/kg group, and a decrease in serum T3 and T4 values in the male rats in the 125 mg/kg group, and thyroid follicular epithelial cell hypertrophy was observed in some of the female rats in the 125 mg/kg group. These findings were concluded to be the result of endocrine-mediated effects of the chemical on thyroid function. In addition, increased liver weight, abnormal histological findings in the liver, and abnormal biochemical parameters related to liver function were observed in male and/or female rats in 5 mg/kg group and higher dose groups. The no-observed-effect level for 4,4′-butylidenebis(2-tert-butyl-5-methylphenol) was concluded to be <5 mg/kg/day. In the uterotrophic assay of 3-(dibutylamino)phenol, female SD rats were subcutaneously injected with the chemical at doses of 0, 100, 300, and 1,000 mg/kg on each of 3 days from postnatal day 20 to day 22, and no changes were observed. In the Hershberger assay of 3-(dibutylamino)phenol, the test chemical was orally administered at doses of 0, 50, 200, and 400 mg/kg/day to castrated male SD rats for ten consecutive days beginning on postnatal day 56, and no changes were observed. On the other hand, when this test chemical was orally administered at doses 0, 30, 100, and 300 mg/kg/day for at least 28 days in the subacute oral toxicity study, thyroid weight increased in the male rats in the 300 mg/kg group, thyroid follicular epithelial cell hypertrophy was observed in a small number of male rats in the 300 mg/kg group, serum T3-values decreased in the female rats in the 300 mg/kg group, and a tendency for TSH-values to increase was observed in the male and female rats in the 300 mg/kg group. Therefore, 3-(dibutylamino)phenol was also concluded to have slight anti-thyroid acting effects as the endocrine-mediated effects. On the other hand, increased hemosiderin deposition in the spleen, increased spleen weight, hematological abnormalities, and squamous epithelial hyperplasia of the forestomach were detected in male and/or female rats in the 100 and/or 300 mg/kg groups, and thus the no-observed-effect level for 3-(dibutylamino)phenol was concluded to be 30 mg/kg/day.
Keywords: 4,4′-Butylidenebis(2-tert-butyl-5-methylphenol); 3-(Dibutylamino)phenol; Endocrine effects; Enhanced Test Guideline 407; Hershberger assay; Rat; Uterotrophic assay
Sulfotransferase 1A1 and glutathione S-transferase P1 genetic polymorphisms modulate the levels of urinary 8-hydroxy-2′-deoxyguanosine in betel quid chewers by Ruey-Hong Wong; Chiung-Wen Hu; Ching-Ying Yeh; Mu-Rong Chao; Chin-Chun Chen; Jun-Huang Huang; Shih-Hsien Chang; Shin-I Lee; Hong-Shen Lee (pp. 313-321).
Betel quid chewing has been associated with several human cancers. However, the role of betel quid in carcinogenesis remains uncertain. Piper betle contains high concentrations of safrole (an inducer of DNA oxidative damage). Safrole may be metabolized by hepatic sulfotransferase 1A1 (SULT1A1), or glutathione S-transferases (GSTM1, GSTT1, and GSTP1). Thus, we investigated the association of genetic polymorphisms of SULT1A1, GSTM1, GSTT1, and GSTP1 with DNA oxidative damage among betel quid chewers. A biomarker for oxidative stress, urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) level, was analyzed using isotope-dilution LC–MS/MS in 64 betel quid chewers and 129 non-betel quid chewers. Data on demographics and habits (smoking, alcohol drinking, and betel quid chewing) were obtained from questionnaires. Our results revealed that urinary 8-OHdG level was higher in chewers with SULT1A1 Arg-His genotype than in chewers with SULT1A1 Arg-Arg genotype. Urinary 8-OHdG level was also higher in chewers with GSTP1 Ile-Ile genotype. Furthermore, the combined effect of SULT1A1 and GSTP1 genotypes on urinary 8-OHdG was evaluated. Non-chewers with both SULT1A1 Arg-Arg and GSTP1 Val-Val/Ile-Val (reference group) had the lowest mean level (3.6 ng/mg creatinine), whereas chewers with either SULT1A1 Arg-His or GSTP1 Ile-Ile had the highest 8-OHdG mean level (6.2 ng/mg creatinine; vs. reference group, P = 0.04). Chewers with both of SULT1A1 Arg-Arg and GSTP1 Val-Val/Ile-Val (4.6 ng/mg creatinine), and non-chewers with either SULT1A1 Arg-His or GSTP1 Ile-Ile (4.7 ng/mg creatinine) had a moderately increased 8-OHdG level. Thus, the susceptible SULT1A1 and GSTP1 genotypes may modulate increased DNA oxidative stress elicited by betel-quid chewing.
Keywords: Betel-quid chewing; SULT1A1 gene; GSTP1 gene; DNA oxidative stress; Urinary 8-hydroxy-2′-deoxyguanosine
Arachidonic acid pathway activates multidrug resistance related protein in cultured human lung cells by Abdelrahman Torky; Anja Raemisch; Felix Glahn; Heidi Foth (pp. 323-332).
Primary cultures of human lung cells can serve as a model system to study the mechanisms underlying the effects of irritants in air and to get a deeper insight into the (patho)physiological roles of the xenobiotic detoxification systems. For 99 human lung cancer cases the culture duration for bronchial epithelium and peripheral lung cells (PLC) are given in term of generations and weeks. Using this system, we investigated whether and how prostaglandins (PG) modify multidrug resistance related protein (MRP) function in normal human lung cells. PGF2α had no effect on MRP function, whereas PGE2 induced MRP activity in cultured NHBECs. The transport activity study of MRP in NHBEC, PLC, and A549 under the effect of exogenously supplied PGF2α (10 μM, 1 day) using single cell fluorimetry revealed no alteration in transport activity of MRP. PG concentrations were within the physiological range. COX I and II inhibitors indomethacin (5, 10 μM) and celecoxib (5, 10 μM) could substantially decrease the transport activity of MRP in NHBEC, PLC, and A549 in 1- and 4-day trials. Prostaglandin E2 did not change cadmium-induced caspase 3/7 activation in NHBECs and had no own effect on caspase 3/7 activity. Cadmium chloride (5, 10 μM) was an effective inducer of caspase 3/7 activation in NHBECs with a fivefold and ninefold rise of activity. In primary human lung cells arachidonic acid activates MRP transport function only in primary epithelial lung cells by prostaglandin E2 but not by F2α mediated pathways and this effect needs some time to develop.
Keywords: Human lung cells; MRPs; Immunocytochemistry; Transport; PGs; COX inhibitors
Some molecular descriptors for non-specific chromosomal genotoxicity based on hydrophobic interactions by Susanne B. Dorn; Gisela H. Degen; Hermann M. Bolt; Jaap van der Louw; Frederique A. A. van Acker; Diels J. den Dobbelsteen; Jos P. M. Lommerse (pp. 333-338).
A concept relating the lipophilicity of chemicals with their genotoxicity on a chromosomal level had been generated by Schultz and Önfelt (Chem Biol Interact 126:97–123, 2000). It was shown that aneuploidy in Chinese hamster V79 cells was elicited by lipophilic chemicals at concentrations related to their hydrophobicity (log P), whereas toxicants with a specific mode of action acted at concentrations consistently lower than predicted based on log P. We have now combined available data sets on aneuploidy/micronucleus formation with procedures used in QSAR modelling, in order to find new molecular descriptors for modelling non-specific chromosomal genotoxicity, and to optimise combinations thereof. Molecular structures of 26 chemicals, including steroids, were converted into single 3D models using Corina (version 3.20), and 11 descriptors of molecular properties were calculated. The data of 16 compounds assigned to a non-specific mode of action were imported into the QSAR module of the software package Cerius2 (version 4.10). Applying genetic function approximation (GFA), linear equations were set up relating molecular descriptors with experimental concentrations at which doubling of micronuclei occurred in V79 cells (exp −log C). The number of variables (molecular descriptors) was limited to a maximum of three, and linear and quadratic terms were allowed. Based on the descriptions provided by the GFA procedure, log P was the most suitable single property to describe non-specific genotoxicity [r 2 = 0.88], confirming the original concept of Schultz and Önfelt. Using more descriptors (up to three in combination) resulted in an optimization of correlations up to r 2 = 0.97. Such optimal correlation coefficients were obtained by combinations (a) of the numbers of hydrogen bond acceptors, the polar surface and total surface areas of molecules on one hand, and by (b) the dipole moment, polar surface and total surface descriptors on the other hand. In essence, the relation of polar surface to the total molecular surface appears pivotal to determine the non-specific chromosomal genotoxicity of lipophilic compounds.
Keywords: Genotoxicity; Non-specific genotoxicity; Aneuploidy; Micronucleus; V79 cells; Molecular descriptors; QSAR
Some molecular descriptors for non-specific chromosomal genotoxicity based on hydrophobic interactions
by Susanne B. Dorn; Gisela H. Degen; Hermann M. Bolt; Jaap van der Louw; Frederique A. A. van Acker; Diels J. van den Dobbelsteen; Jos P. M. Lommerse (pp. 339-339).