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Archives of Toxicology (v.73, #10-11)

An intra-laboratory validation of the Integrated Model for the Differentiation of Skin Reactions (IMDS): discrimination between (photo)allergic and (photo)irritant skin reactions in mice by H-W. Vohr; J. Blümel; A. Blotz; B. Homey; H. J. Ahr (pp. 501-509).

We recently presented a modified local lymph node test which made it possible to quickly and reliably differentiate between irritative and allergic skin reactions with extremely simple parameters. The Integrated Model for the Differentiation of Skin Reactions (IMDS) test combines measurement of cell proliferation in draining lymph nodes with measurement of primary ear swelling after topical application of the test substance on three consecutive days. In contrast to the `classic' skin sensitisation test in guinea-pigs the IMDS test is considerably faster and is based on objective measured data, not subjective skin evaluations. Like the Local Lymph Node Assay (LLNA), measurement of allergic potential in the IMDS test is based on the underlying immunological mechanisms, but also considers the behaviour of immune competent cells following non-specific activation by irritants. In addition, the IMDS test can employ UV radiation after application of the substance and, therefore, make differentiation possible between different types of skin photoreaction (photoallergy and photoirritation) after both topical and systemic adminis-tration. Attempts to achieve this kind of discrimination with the LLNA necessitate considerably greater expenditure, as proliferation in the draining lymph nodes can also be induced by moderate to extreme (photo)irritants. In a previous paper in which we presented the IMDS test, we examined each type of reaction in reference to one single standard; the next logical step was therefore a broad-based intra-laboratory validation. An important factor in the validation was the use of standards that had been thoroughly examined in both guinea pig and mouse systems and were also relevant with regard to estimation of the risk for humans. The data presented here show that the IMDS is a simple and reliable tool for obtaining fast and reproducible assessments of potential (photo)allergic and (photo)irritant skin reactions to substances.

Keywords: Key words Integrated Model for the Differentiation of Skin Reactions (IMDS); Local Lymph Node Assay (LLNA); Contact hypersensitivity; Irritant contact dermatitis; Photoallergy

A meta-analysis for neurobehavioural results due to occupational lead exposure with blood lead concentrations <70 μg/100 ml by Monika Meyer-Baron; Andreas Seeber (pp. 510-518).

The size of performance effects caused by exposure to inorganic lead was determined by a meta-analytical procedure. Twenty-two studies covering exposure conditions of <70 μg/100 ml blood lead concentration were considered as to whether the methods of recording performance deficits were comparable. As a consequence of different test procedures and insufficient documented test results only 13 tests out of 12 studies could be included in the analysis. For the tests Block Design, Logical Memory and Santa Ana performance deficits were found, which may be interpreted as `small' effects in accordance with a convention for evaluating effect sizes. For the example of Block Design it could be shown that these effects are nevertheless serious. The extent of the exposure related decrease of performance was comparable with those changes of performance which can be expected during aging of up to 20 years. Subsequently, a blood lead concentration of 70 μg/100 ml cannot be considered as a safe limit against long-term decreases of psychological performance.

Keywords: Key words Inorganic lead; Neurotoxic effects; Threshold limit setting

Cadmium in milk and mammary gland in rats and mice by Kierstin Petersson Grawé; Agneta Oskarsson (pp. 519-527).

The purpose of the present investigation was to study the uptake of cadmium in mammary tissue, effects on milk secretion and composition, and lactational transport of cadmium to the sucklings. Cadmium exposure during lactation resulted in retention of cadmium in the mammary tissue in mice and rats. The uptake of cadmium in the mammary tissue was rapid, as shown in lactating mice by whole-body autoradiography 4 h after an intravenous injection of a tracer dose of ¹⁰⁹CdCl₂. Retention of cadmium in kidneys of suckling pups was observed in the autoradiograms at 7 days after exposure of the dams. Lactating rats were intravenously infused with ¹⁰⁹CdCl₂ in 0.9% saline via osmotic minipumps from day 3 to day 16 after parturition. The cadmium dose given was 0, 8.8, 62 and 300 μg Cd/kg body wt. per day. Plasma and milk were collected at day 10 and 16 after parturition. Plasma cadmium levels in dams increased from day 10 to day 16. Cadmium levels were higher in milk than in plasma, with milk/plasma ratios varying from 2 to 6. Zinc levels in milk were positively correlated to cadmium levels in milk (r ²=0.26; P=0.03). In milk, ¹⁰⁹Cd was distributed in fat (46–52%), casein fraction (40–46%), and whey fraction (6–8%). There was a high correlation between cadmium concentrations in pups' kidney and cadmium concentrations in dam's milk (r ²=0.98; P < 0.001). Of the cadmium dose given to the dams <0.05% was retained in the litters on day 16 of lactation. No effects were observed due to cadmium exposure on body weight in pups or dams. Cadmium treatment did not cause any effect on the lactose or protein concentration in milk, the concentrations of DNA, RNA or the ratio RNA/DNA in the mammary gland. Histological evaluation of mammary tissue did not reveal any abnormalities at any dose level. ¹⁰⁹Cd was bound to metallothionein in mammary tissue. The fraction of radiolabelled cadmium bound to metallothionein increased in a dose-dependent manner in both the liver (88–98%) and mammary tissue (57–80%). The present results indicate a low transfer of cadmium to the suckling pup, which might be due to binding of cadmium to metallothionein in the mammary tissue. However, during the susceptible developmental period even a low cadmium exposure may be of concern.

Keywords: Key words Cadmium; Lactation; Mammary gland; Milk; Metallothionein

NAD(P)H quinone oxidoreductase 1 codon 609 polymorphism and its association to colorectal cancer by V. Harth; S. Donat; Y. Ko; J. Abel; H. Vetter; T. Brüning (pp. 528-531).

The present study used a rapid and single-step method for genotyping of NAD(P)H quinone oxidoreductase (NQO1) codon 609 polymorphism using real-time polymerase chain reaction (PCR)-analysis and subsequent melting curve analysis for the analysis of allelic distribution of NQO1. The design was a case control study of 323 Caucasians with colorectal cancer and 205 healthy controls. There was no difference in the frequencies of the mutated NQO1 allele (NQO1*2): 0.190 for control individuals and 0.195 for cancer patients, respectively (P=0.947). When this allelic distribution was further compared between non-smoking and smoking colorectal cancer patients, it appeared that the frequency of the wild-type allele NQO1*1 was higher in the smoking than in the non-smoking group [Odds ratio (OR), 0.434; 95% confidence interval (CI), 0.13–1.42]. This observation may suggest a protective role of the NQO1 wild-type allele in colon cancer susceptibility of individuals exposed to NQO1-inducing chemicals.

Keywords: Key words NQO1 polymorphism; Real-time PCR; Colorectal cancer

CYP2A6 genetic polymorphisms and liver microsomal coumarin and nicotine oxidation activities in Japanese and Caucasians by Kiyoshi Inoue; Hiroshi Yamazaki; Tsutomu Shimada (pp. 532-539).

Genotypes of CYP2A6, namely CYP2A6 * 1 (wild-type), CYP2A6 * 2, and CYP2A6 * 3, were examined in liver DNA of 39 Japanese and 43 Caucasians using two-step polymerase chain reaction (PCR) methods. We first amplified a DNA fragment (1725 bp) located between near middle of exon 1 and end of exon 4 of the CYP2A6 gene and further amplified using a forward primer 't' or 'mut' (middle of exon 3) and a reverse primer 'E3R' (middle of intron 3) for the detection of CYP2A6 * 2-genetic polymorphism. The 1725 bp fragment was also used for the amplification between exon 3 and near middle of intron 3 of the CYP2A6 gene and the fragment thus obtained digested with XcmI or DdeI to detect and confirm the CYP2A6 * 2- and CYP2A6 * 3-types, respectively. Only one DNA sample from a Japanese origin (J18) was not amplified by CYP2A6-specific primers; liver microsomes from this individual had very low activity of coumarin 7-hydroxylation and were devoid of protein(s) immunoreactive to anti-CYP2A6 antibody. Thus, this individual was suggested to be due to the gene deletion in CYP2A6. By analyzing the remaining 38 Japanese and 43 Caucasians, we found that there were no cases of CYP2A6 * 3-type polymorphism in the samples examined in this study, and no cases of CYP2A6 * 2-type polymorphism in the Japanese samples. Of Caucasians studied two individuals were classified into heterozygous CYP2A6 * 1/ * 2-type. Liver microsomal coumarin 7-hydroxylation activities in these two Caucasians were found to be lower than those of the other 41 Caucasians. Kinetic analysis showed that two CYP2A6 * 1/ * 2 individuals had a very low ratio of V _max to K _m for nicotine C-oxidation as well as coumarin 7-hydroxylation in liver microsomes, compared with those of homozygous CYP2A6 * 1-type. These results suggest that among 39 Japanese and 43 Caucasians examined one Japanese is classified to be CYP2A6 gene deletion and two Caucasians are heterozygous CYP2A6 * 1/ * 2-genotype. Thus the race-related differences in the occurrence of CYP2A6 genetic polymorphisms were supported.

Keywords: Key wordsCYP2A6 polymorphism; Coumarin; Nicotine; Japanese; Caucasian

Effect of hyperoxia on rat pulmonary and hepatic cytochrome P450 monooxygenases by Ram K. Sindhu; Hironori Sakai; Yutaka Kikkawa (pp. 540-546).

Exposure of adult male rats to hyperoxia (O₂ > 95%) resulted in a tendency for all of the components of the pulmonary cytochrome P450 (P450) system to increase at 48 h after the exposure. However, the most pronounced effect of hyperoxia was observed on pulmonary ethoxycoumarin O-deethylase and ethoxyresorufin O-deethylase activities which were induced 4- and 25-fold respectively after 48 h. In the liver, P450 and NADH b₅ reductase were increased after 48 h, while other components of the monooxygenase system remained unchanged. In the hepatic microsomes, contrary to the lungs, aminopyrine N-demethylase activity was decreased after 24 h of hyperoxic exposure (P < 0.05) and returned to the control level by 48 h. Similar changes were observed in benzphetamine N-demethylase activity. Aniline hydroxylase activity was decreased after 8 h of hyperoxic exposure (P < 0.01) and remained decreased at 24 h (P < 0.01) and 48 h (P < 0.05). The level of induction of ethoxycoumarin O-deethylase and ethoxyresorufin O-deethylase activities, however, was almost similar in the liver to that observed in the lungs.

Keywords: Key words Hyperoxia; CYP1A1; CYP1A2; Aryl hydrocarbon receptor; Oxidized tryptophan

Selective agonists of retinoic acid receptors: comparative toxicokinetics and embryonic exposure by Husam M. M. Arafa; Mohamed M. A. Elmazar; Farid M. A. Hamada; Uwe Reichert; Braham Shroot; Heinz Nau (pp. 547-556).

Three biologically active synthetic retinoids were investigated that bind selectively to retinoic acid receptors RARs (α, β and γ). The retinoids were previously demonstrated to have different teratogenic effects in the mouse in terms of potency and regioselectivity. The teratogenic potency rank order (α >β >γ) was found to be more or less compatible with the receptor binding affinities and transactivation potencies of the retinoid ligands to their respective receptors. The RARα agonist (Am580; CD336) induced a wide spectrum of malformations; CD2019 (RARβ agonist) and especially CD437 (RARγ agonist) produced more restricted defects. In the current study we tried to address whether the differences in teratogenic effects are solely related to binding affinity and transactivation differences or also due to differences in embryonic exposure. Therefore, transplacental kinetics of the ligands were assessed following administration of a single oral dose of 15 mg/kg of either retinoid given to NMRI mice on day 11 of gestation. Am580 was rapidly transferred to the embryo resulting in the highest embryonic exposure [embryo to maternal plasma area under the time vs concentration curve (AUC)_0–24 hratio (E/M) was 1.7], in accordance with its highest teratogenic potency. The low placental transfer of CD2019 (E/M of 0.3) was compatible with its lower teratogenic potential. Of major interest was the finding that the CD437, though being least teratogenic, exhibited considerable embryonic exposure (E/M of 0.6). These findings suggest that both the embryonic exposure and receptor binding transactivation selectivity are crucial determinants of the teratogenicity of these retinoid ligands.

Keywords: Key words Selective retinoids; Toxicokinetics; Embryonic exposure; Area under the time vs concentration curve (AUC); Retinoids

Ciprofloxacin causes cytoskeletal changes and detachment of human and rat chondrocytes in vitro by Monika Egerbacher; Gertrude Seiberl; Birgitt Wolfesberger; Ingrid Walter (pp. 557-563).

Quinolones cause damage of articular cartilage in different species by forming chelate complexes with divalent cations and inducing magnesium deficiency. Cations are important for regular function of integrins, a group of transmembrane proteins which connect extracellular matrix proteins with the intracellular cytoskeleton. We have shown that cultivation of rat chondrocytes in ciprofloxacin (CFX)-supplemented and Mg²⁺-free medium led to pronounced changes in the cytoskeleton and decreased adhesion of cells to the culture dish. In order to test whether or not these effects are species-specific, we extended our studies on human chondrocytes. Human chondrocytes cultivated in CFX-supplemented medium (10, 40, 80 and 160 μg/ml) or Mg²⁺-free medium showed decreased ability to adhere to growth support, cell shape changes, and alterations in actin and vimentin cytoskeleton in a concentration dependent manner. Attachment of human chondrocytes to collagen type II coated cover slips was reduced to 90% in CFX group and 75% in Mg²⁺-free group on day 1. This effect even increased after 4 days of culture in the respective medium (32% in CFX and 58% in Mg²⁺-free group). We concluded that Mg²⁺ deficiency is exerted via integrins, resulting in decreased ability to attach to extracellular matrix proteins and cytoskeletal changes. These effects are not species-specific. The attachment assay proves to be an easy to use experimental set-up to test ciprofloxacin and other quinolones for their chondrotoxic effects.

Keywords: Key words Chondrocytes; Fluoroquinolones; Magnesium; Integrins; Cytoskeleton

Chondrotoxicity of ciprofloxacin in immature Beagle dogs: immunohistochemistry, electron microscopy and drug plasma concentrations by R. Stahlmann; S. Kühner; M. Shakibaei; R. Schwabe; J. Flores; S. A. Evander; D. C. van Sickle (pp. 564-572).

The systemic effects of ciprofloxacin in immature Beagles were studied. Dogs of 10–11 weeks were dosed orally for 5 days with 0 (n=3), 30 (n=5) and 200 (n=5) mg ciprofloxacin/kg body wt. Plasma concentrations were measured by high-performance liquid chromatography (HPLC) 1 h after dosing (assuming to be peak concentrations). In view of the high doses used, the plasma concentrations were rather low and declined during the study period. For example, plasma concentrations in the high dose group were 6.6 ± 0.9 mg/l (day 1), 3.9 ± 1.4 mg/l (day 3), and 2.6 ± 1.6 mg/l (day 5). In control dogs and in dogs treated with the low dose of ciprofloxacin no pathological changes were seen by light microscopy. However, cleft formation and erosions were observed in joint cartilage from two of five dogs treated with 200 mg/kg. It is noteworthy that despite the high dose used cartilage lesions were not detectable in all five dogs of this group by light microscopy. Using antibodies against cell membrane receptors (e.g. the α₅β₁-integrin) or matrix components (fibronectin, collagen II) the articular cartilage effects were studied in detail by immunohistochemistry. The most sensitive alteration was an increase in fibronectin which was detectable in the vicinity of the lesions in cartilage samples from the group of dogs administered the high dose. No clear-cut changes were seen with the use of antibodies against other matrix components. Electron microscopy revealed typical alterations in chondrocytes from dogs treated with ciprofloxacin: e.g., swollen mitochondria and enlarged rough endoplasmic reticulum. These changes were much more pronounced in dogs from the high dose group than in dogs from the low dose group. Our main conclusion is that after oral administration ciprofloxacin exhibits rather low chondrotoxicity, even in the most sensitive species known to date. This correlates with the findings in humans that ciprofloxacin seems to be less chondrotoxic than pefloxacin or other quinolones.

Effects of magnesium deficiency on joint cartilage in immature Beagle dogs: immunohistochemistry, electron microscopy, and mineral concentrations by R. Stahlmann; S. Kühner; M. Shakibaei; J. Flores; J. Vormann; D. C. van Sickle (pp. 573-580).

Quinolone-induced chondrotoxicity is possibly associated with the magnesium-chelating properties of quinolones. This toxic effect seems to be restricted to a rather short time period during postnatal development as shown in rats and dogs. We studied developmental changes of the integrin pattern on canine chondrocytes (e.g. the α_vβ₃- or α₅β₁-integrin), because integrin function depends on divalent cations, as well as the matrix composition (e.g., collagen type II, fibronectin), in 11-, 18-, and 55-week-old Beagles (n=8) by immunohistochemistry. We also analyzed the magnesium and calcium content by atomic absorption spectroscopy in cartilage and bone and studied the effects of a magnesium-deficient diet on joint cartilage in four immature Beagles (18 weeks old at necropsy). The dogs were fed the magnesium-deficient diet for 40 to 46 days. All dogs exhibited gait alterations (`limping') after 4 weeks on the magnesium-deficient diet. Male, magnesium-deficient dogs exhibited pronounced weakness in their front legs; in one of these dogs the front legs were hyperextended to a 90° angle. We observed no significant differences in the integrin pattern in samples from dogs at different developmental stages or in magnesium-deficient dogs in comparison to age-matched controls. Localization of fibronectin in the joint cartilage was found to vary with the age of the dogs as well as with the site of collection. In the middle zone of immature joint cartilage, corresponding to the predilective site of quinolone-induced cartilage lesions, we observed a slight increase in staining with the fibronectin antibody in some samples from magnesium-deficient dogs. Electron microscopy revealed alterations in chondrocytes from the magnesium-deficient dogs (e.g., swollen mitochondria and enlarged endoplasmic reticulum) which are also seen after treatment with quinolones. In summary, we found no significant differences of the integrin pattern on chondrocytes from joint cartilage of dogs at various developmental stages. However, magnesium deficiency in immature dogs induced similar clinical symptoms as quinolone treatment as well as distinct alterations in chondrocytic fibronectin staining and their ultrastructure. This corroborates our findings in rats where magnesium chelation is an important event in quinolone-induced chondrotoxicity.

Non-N-methyl-D-aspartate (NMDA) receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo(f)quinoxaline-7-sulphonamide (NBQX) decreases functional disorders in cytotoxic brain oedema by A. Häntzschel; K. Andreas (pp. 581-587).

N-methyl-D-aspartate (NMDA) and non-NMDA receptors were found to be involved in development of functional disorders caused by hexachlorophene. In order to specify the role of glutamate receptors we studied the protective effects of the selective antagonist of the kainate/(±)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor/channel 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulphonamide disodium (NBQX) and of the non-competitive NMDA receptor antagonist ifenprodil tartrate on coordinative motor behaviour of adult male Wistar rats as assessed in a simple `ladder-test'. Neurotoxic injury of the cerebrum after hexachlorophene administration and putative amelioration after treatment with test substances was demonstrated histologically. Hexachlorophene-induced motor disturbance remitted spontaneously when stopping the noxis, but remittance occurred significantly earlier when NBQX [0.45 and 0.6 mg/kg intraperitoneal (i.p.)] was applied as well. Ifenprodil (0.15 to 1.2 mg/kg) did not improve the motor function. Vacuolation of white matter of the whole cerebrum was observed after 3 weeks of treatment with hexachlorophene. These morphological alterations caused by hexachlorophene treatment [central nervous system (CNS) vacuolation] spontaneously revert only after 5–6 weeks. The 5-day duration with test substances was too short for remission of vacuolation which thus may not apply to the situation after treatment with glutamate antagonists, despite improvement of motor function. The results suggest that kainate/AMPA receptor channels are at least partially involved in the mechanism of brain damage induced by hexachlorophene, however, the polyamine binding site of the NMDA receptor evidently is not involved.

Keywords: Key words Hexachlorophene; Coordinative motor behaviour; Cytotoxic brain oedema; Rat histology; NMDA and non-NMDA antagonists

Effect of polychlorinated biphenyls on production of reactive oxygen species (ROS) in rat synaptosomes by Ø.A. Voie; F. Fonnum (pp. 588-593).

In this paper the effect of polychlorinated biphenyls (PCBs) on the production of reactive oxygen species (ROS) in rat synaptosomes is elucidated. The effect of methylmercury (MeHg) on rat synaptosomes was included as a positive control since several studies have investigated the ability of this substance to produce ROS. The exposure of the synaptosomes to the congener 2,2-dichlorobiphenyl (2,2′-DCB; 12.5 μM) produced a linear increase in the formation of 2′,7′-dichlorofluorescein (DCF) as a measure for the production of ROS. The congeners 2,2′-DCB (12.5 μM) and 3,3′-DCB (12.5 μM) stimulated, as expression of ROS production, a significant increase in DCF formation formation compared to the control. The congeners 2-chlorobiphenyl (2-CB) and 2,2′,6-trichlorobiphenyl (2,2,6′-TCB) were active at 50 μM, whereas 2,2′,4,4′,5,5′-hexachlorobiphenyl (2,2′,4,4′,5,5′-HCB), 4,4′-DCB and 2,2′,6,6′-tetrachlorobiphenyl (2,2′,6,6′-TeCB) were not active at this concentration. The increased formation of ROS in response to 2,2′-DCB and MeHg in the synaptosomes was dependent on extracellular Ca²⁺. A phospholipase C inhibitor, U73122, was shown to significantly decrease the ROS formation induced by 2,2′-DCB, but did not reduce the ROS formation induced by MeHg. Ethanol (1%), a phospholipase D modulator, reduced the ROS formation induced by MeHg and by 2,2′-DCB by 33 and 52%, respectively. Wortmannin (25 nM), an inhibitor of phosphatidylinositol 3-kinase, completely inhibited the ROS formation induced by MeHg and 2,2′-DCB. It appears that the ROS-stimulating PCBs are the same congeners found to be neuroactive in other types of study. Phospholipase C and D and phosphatidylinositol 3-kinase seem to be involved in the intracellular signalling system that leads to ROS formation during PCB exposure.

Keywords: Key words Polychlorinated biphenyls (PCB); Synaptosomes; Reactive oxygen species (ROS); Free radicals; Mechanism

A hepatotoxic dose of acetaminophen modulates expression of BCL-2, BCL-X_L, and BCL-X_S during apoptotic and necrotic death of mouse liver cells in vivo by Sidhartha D. Ray; Nilameni Jena (pp. 594-606).

The protein BCL-X_L and protein product of proto-oncogene bcl-2 act as apoptosis antagonists, and BCL-X_S serve as a dominant death promoter, including apoptosis following exposure to chemotherapeutic drugs. This investigation examined whether some aspects of the highly integrated process of acetaminophen (AAP)-induced hepatotoxicity involve down-regulation or upregulation of expression of BCL-2, BCL-X_L and BCL-X_S in mouse liver in vivo. Male ICR mice (CD-1; 35–45 g) were treated ip with a hepatotoxic dose of AAP (500 mg/kg) and sacrificed 0, 6, and 18 h later. Blood was collected upon sacrifice for determination of serum alanine aminotransferase (ALT) activity and the liver was sectioned for histopathological diagnosis of necrosis/apoptosis. Portions of liver tissues were also used for DNA extraction (for gel electrophoresis) and Western blot analysis. This study demonstrates that administration of a hepatotoxic dose of AAP to ICR mice results in severe liver injury (ALT leakage >200-fold at 6 h and >600-fold at 18 h) leading to massive cell death by apoptosis (diagnosed by nuclear ultrastructure, histopathology, and DNA ladder), in addition to necrosis coupled with spectacular changes in the BCL-X_L expression (6 and 18 h after AAP administration). Western blot analysis of the liver proteins revealed that mouse liver expresses two proteins, BCL-X_L and BCL-X_S, and does not express BCL-2. As the toxicity progressed, during 6 and 18 h post-AAP administration, the BCL-X_L protein band shifted to a slower mobility band which might represent a phosphorylated form of BCL-X_L. Appearance of this higher molecular weight BCL-X_L protein band correlated with massive apoptotic death of liver cells along with ladder-like DNA fragmentation. In the same time period, death inhibitory gene bcl-2 remained unexpressed, and the level of expression of BCL-X_S remained unaltered. Whether the consistent level of expression of BCL-X_S reflected inability of AAP to influence its expression remains unknown. Unaltered expression of BCL-X_S in the near total absence of BCL-2 expression raises questions regarding the death promoting role of BCL-X_S in vivo. The precise role of modified form of BCL-X_L remains elusive. However, this study may have demonstrated for the first time drug-induced changes in the expression of anti-apoptotic gene BCL-X_L, and a positive link between AAP-induced apoptotic death and modification of BCL-X_L protein in vivo.

Keywords: Key words Acetaminophen; Hepatotoxicity; Apoptosis; bcl-XL expression; DNA fragmentation

Metabolites of the biocide o-phenylphenol generate oxidative DNA lesions in V 79 cells by P. Henschke; E. Almstadt; S. Lüttgert; K. E. Appel (pp. 607-610).

Incubation of the o-phenylphenol (OPP) metabolites, o-phenylhydroquinone (PHQ) and o-phenylbenzoquinone (PBQ) with V 79 Chinese hamster cells led to a significant enhancement of the amount of 8-hydroxy-2′-deoxyguanosine (8-OH-dG) in nuclear DNA. With OPP no distinct induction of this lesion could be observed. In addition, PHQ and PBQ were able to generate DNA single-strand breaks (DNA SSB), while OPP failed to induce this lesion. All incubations were performed for 1 h without exogenous metabolic activations and the lowest effective concentration tested was 20 μM. It is concluded that these metabolites may contribute to the carcinogenicity of OPP and sodium o-phenylphenolate (SOPP) observed in rats, by generating reactive oxygen species (ROS) through their redox cycling properties.

Keywords: Key wordsortho-Phenylphenol; Phenylhydro-quinone; Phenylbenzoquinone; Carcinogenicity; Oxidative DNA damage

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Archives of Toxicology (v.73, #10-11)