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Archives of Toxicology (v.81, #10)

Renal deterioration caused by carcinogens as a consequence of free radical mediated tissue damage: a review of the protective action of melatonin by Fatih Gultekin; Hicran Hicyilmaz (pp. 675-681).

This brief review summarizes some of the publications that document the preventive role of melatonin in kidney damage caused by carcinogens such as 2-nitropropane, arsenic, carbon tetrachloride, nitrilotriacetic acid and potassium bromate. Numerous chemicals generate excessive free radicals that eventually induce renal worsening. Melatonin partially or totally prevents free radical mediated tissue damages induced by many carcinogens. Protective actions of melatonin against the harmful effects of carcinogens are believed to stem from its direct free radical scavenging and indirect antioxidant activities. Dietary or pharmacologically given melatonin may attenuate the oxidative stress, thereby mitigating the subsequent renal damage.

Keywords: Melatonin; Kidney; Free radical; 2-Nitropropane; Arsenic; Carbon tetrachloride; Nitrilotriacetic acid; Potassium bromate

Endogenous thiols enhance thallium toxicity by Sergio Montes; Luz Soriano; Camilo Ríos; Antonio Monroy-Noyola (pp. 683-687).

Either L-methionine (L-met) or L-cysteine (L-cys), given alone and in combination with Prussian blue (PB) was characterized as treatment against acute thallium (Tl) toxicity in rats. Animals were intoxicated with 32 mg/kg Tl acetate corresponding to rat LD₅₀. Antidotal treatments were administered during 4 days, as follows: (1) vehicle, (2) L-met 100 mg/kg i.p. twice a day, (3) L-cys 100 mg/kg i.p. twice a day, (4) PB 50 mg/kg oral, twice a day, (5) L-met + PB and (6) L-cys + PB. Mortality was as follows: control 50%; L-met 80%; L-cys 80%; PB 20%; L-met + PB 90% and L-cys + PB 100%. In a different experiment, using 16 mg/kg of Tl, tissue levels of this metal were analyzed. PB treatment statistically diminished Tl content in body organs and brain regions (P < 0.01). Whereas, separate treatments of L-met and L-cys failed to decrease Tl content in organs and brain regions; while its administration in combination with PB (L-met + PB and L-cys + PB groups) lowered Tl levels in body organs in the same extent as PB group. Results indicate that L-met and L-cys administered alone or in combination with PB should not be considered suitable treatments against acute Tl toxic effects because this strategy failed to prevent mortality and Tl accumulation in brain.

Keywords: Thallium; Thallium antidotes; Prussian blue; L-methionine; L-cysteine; Brain

Comparative hydrolysis of O-hexyl O-2,5-dichlorophenyl phosphoramidate and paraoxon in different tissues of vertebrates by Antonio Monroy-Noyola; Patricia Rojas; Eugenio Vilanova; Miguel A. Sogorb (pp. 689-695).

The Ca²⁺-dependent and EDTA-resistant hydrolysis of O-hexyl O-2,5-dichlorophenyl phosphoramidate (HDCP) and paraoxon was studied in serum and subcellular fractions of liver, kidney and brain of hen, rat and rabbit. HDCP was the best substrate among all the tissues studied, except that of rabbit serum which showed the highest Ca²⁺-dependent paraoxon hydrolysing activity (paraoxonase). High HDCP hydrolysing activity (HDCPase) was detected in the brain tissue of the three species studied, whereas low or no paraoxonase was found. The HDCPase/paraoxonase ratio of Ca²⁺-dependent hydrolysing activities ranged from 0.5 to 83 for tissues of the same species. EDTA-resistant HDCPase activity was more than 50% of the total activities in hen tissues, with an almost undetectable Ca²⁺-dependent paraoxonase activity in most organs. The same response was observed in rat tissues, except for serum where the Ca²⁺-dependent HDCPase and paraoxonase activities were higher (70 and 25% of total activities, respectively). EDTA-resistant HDCPase and paraoxonase activities represented less than 25% of all activities in rabbit tissues. Paraoxon has traditionally been the substrate for measuring organophosphorus hydrolysing activities. However, HDCP could be a good substrate in addtion to paraoxon for monitoring other phosphotriesterases in biological tissues.

Keywords: Paraoxonase; HDCPase; Phosphotriesterases; Phosphoramidate

Induction of CYP1A1 and CYP2E1 in rat liver by histamine: binding and kinetic studies by Víctor M. Dávila-Borja; Javier A. Belmont; J. Javier Espinosa; Rafael Moreno-Sánchez; Arnulfo Albores; Regina D. Montero (pp. 697-709).

Histamine (HA) may bind to cytochrome P450 (CYP450) in rat liver microsomes. The CYP450-HA complex seems to regulate some cellular processes such as proliferation. In the present work, it is shown that HA increases the activity and protein level of CYP1A1 and CYP2E1, in vivo. CYP1A1 is associated with polycyclic aromatic hydrocarbon-mediated carcinogenesis and CYP2E1 with liver damage by oxidative stress. Studies of enzyme kinetics and binding with rat liver microsomes and supersomes^® were carried out to determine whether HA is a substrate of CYP1A1 and/or CYP2E1. The lack of NADPH oxidation in the presence of HA showed that it is not a substrate for CYP1A1. Activity measurements using the O-dealkylation of ethoxyresorufin indicated that HA is a mixed-type inhibitor of CYP1A1 in both microsomes and supersomes. On the other hand, HA induced a significant NADPH oxidation catalyzed by CYP2E1 supersomes^®, strongly suggesting that HA is a substrate for this isoform. Furthermore, HA is consumed in the presence of CYP2E1-induced microsomes and supersomes, as determined by o-phtalaldehyde complexes with HA by HPLC. The present findings may contribute to understand better the physiological function of CYP450 in relation with inflammation and other physiological processes in which HA may have a relevant role.

Keywords: Histamine; CYP1A1; CYP2E1; Induction; Catalytic inhibition

Genotype and allele frequencies of polymorphic CYP2E1 in the Turkish population by Gulen Ulusoy; Emel Arinç; Orhan Adali (pp. 711-718).

Cytochrome P4502E1 (CYP2E1) gene shows genetic polymorphisms that vary markedly in frequency among different ethnic and racial groups. We studied the genotype distributions and allele frequencies of three CYP2E1 polymorphisms: CYP2E1*5B (RsaI/PstI RFLP, C-1053T/G-1293C SNP, rs2031920 /rs3813867), CYP2E1*6 (DraI RFLP, T7632A SNP, rs6413432), and CYP2E1*7B (DdeI RFLP, G-71T SNP, rs6413420) by PCR/RFLP technique in a sample of 206 healthy subjects representing Turkish population. CYP2E1*5B polymorphism analysis yielded the genotype distribution as 96.12% for *1A/*1A (c1/c1), and 3.88% for *1A/*5B (c1/c2). The genotype frequencies for CYP2E1*6 polymorphism were found as 83.98% for *1A/*1A (T/T), 15.53% for *1A/*6 (T/A) and 0.49% for *6/*6 (A/A). For CYP2E1*7B (G-71T) polymorphism, the genotype frequencies were determined to be 86.89% for *1A/*1A (G/G), 12.62% for *1A/*7B (G/T) and 0.49% for *7B/*7B (T/T). Accordingly, the allele frequencies for *5B, *6 and *7B were 1.94, 8.25, and 6.80%, respectively. The genotype distributions of CYP2E1*5B and *6 in Turkish population were similar to those in other Caucasian populations, while differed significantly from East Asian populations. Recently, a novel and functionally important CYP2E1*7B polymorphism was identified in the promoter region. There have been few studies and limited data on CYP2E1*7B polymorphism frequency in the world and, so far, no information has been available for Turkish population. The genotype frequencies of CYP2E1*7B in Turkish population were found to be similar to those of other Caucasian populations. Population studies like this could be useful in assessing the susceptibility of different populations to chemical-induced diseases, including several types of cancer.

Keywords: CYP2E1 gene; Turkish population; Genetic polymorphism; Allele frequencies; CYP2E1*5B, *6, *7B

Berberine induces apoptosis in SW620 human colonic carcinoma cells through generation of reactive oxygen species and activation of JNK/p38 MAPK and FasL by Wen-Hsiu Hsu; Yih-Shou Hsieh; Hsing-Chun Kuo; Chun-Yuh Teng; Hai-I Huang; Chau-Jong Wang; Shun-Fa Yang; Yi-Sheng Liou; Wu-Hsien Kuo (pp. 719-728).

Berberine is the major constituent of Coptidis Rhizoma with multiple pharmacological activities, including anti-inflammation, promotion of apoptosis and anticancer potential effect. Mitogen-activated protein kinase (MAPK) and reactive oxygen species (ROS) may contribute to the causal relationship between tumorigenesis and pro-apoptotic function. Berberine is studied for the mechanism of its action in apoptotic pathway in human colonic carcinoma cell. Treatment of SW620 cells with 50 μM berberine resulted in activation of the caspase 3 and caspase 8, cleavage of poly ADP-ribose polymerase (PARP) and the release of cytochrome c; whereas, the expression of BID and anti-apoptosis factor c-IAP1, Bcl-2, and Bcl-_XL were decreased markedly. Berberine-induced, dose-dependent induction of apoptosis was accompanied by sustained phosphorylation of JNK and p38 MAPK, as well as generation of the ROS. Furthermore, the induction of apoptosis was alleviated by inhibitors specific for JNK and p38. In addition, there was an increase in the cellular levels of phospho-c-Jun, FasL and t-BID in the berberine-induced apoptosis via the activation of JNK and p38 signaling modules. NAC administration, a scavenger of ROS, reversed berberine-induced apoptosis effects via inhibition of JNK, p38 and c-jun activation, and FasL and t-BID expression. These results leads us to speculate that berberine may play an apoptotic cascade in SW620 cells by activation of the JNK/p38 pathway and induction of ROS production, providing a new mechanism for berberine-induced cell death in human colon cancer cells.

Keywords: Berberine; Colonic carcinoma; ROS; JNK; p38 MAPK

VEGF isoforms and receptors expression throughout acute acetaminophen-induced liver injury and regeneration by Vasilios P. Papastefanou; Evangelos Bozas; Michael G. Mykoniatis; Agni Grypioti; Stavros Garyfallidis; Christos S. Bartsocas; Polyxeni Nicolopoulou-Stamati (pp. 729-741).

Acetaminophen (APAP) is a widely-used analgesic and a known hepatotoxic agent. Vascular endothelial growth factor (VEGF) is a growth factor with multiple functional roles. VEGF plays an important role in angiogenesis and hepatic regeneration. The aim of this study was to determine the expression of VEGF isoforms and its receptors throughout liver regeneration after the administration of a toxic dose of APAP in rats. Ten groups of adult male rats received a dose of 3.5 g/kg b.w. of APAP per os. The rats were killed post administration at 0–288 h. Blood and liver tissue were extracted. Determination of serum transaminases and alkaline phophatase activities was performed. Liver injury and regeneration were assessed with hematoxylin-eosin specimens, morphometric analysis, hepatic thymidine kinase assay and Ki-67 expression. Reverse transcription-polymerase chain reaction and immunohistochemical methods were used for assessment of VEGF isoforms and receptors differential expression. High activities of aspartate aminotransferase were observed at 24 and 36 h with another peak of activity at 192 h post administration. Alanine aminotransferase was highest at 36 h. Alkaline phophatase was increased post 24 h being higher at 72,192 and 240 h. Centrilobular necrosis was observed at 48–72 h and thorough restoration of the liver microarchitecture was observed at 288 h. Liver regeneration lasted from 24–192 h according to the results from thymidine kinase activity and Ki-67 expression. VEGF and VEGF receptor-2 m-RNA levels presented with a three-peak pattern of expression at 12–24, 72–96 and 192–240 h post administration. Significant difference was noted between periportal and centrilobular immunohistochemical expression. VEGF proves to play a critical role during APAP-induced liver regeneration as it presents with three points of higher expression. The first two time points are associated with the initial inflammatory reaction to the noxious stimulus and the hepatocyte regenerative process where as the third one is indicative of the potential involvement of VEGF in processes of remodeling

Keywords: Liver regeneration; Acetaminophen; VEGF; VEGFR1; VEGFR2

Ketoprofen: experimental overview of dermal toxicity by Byoung-Seok Lee; Yang-Gyu Choi; Woo-Chan Son; Kyoung-Mi Jung; Jung-Ju Kim; Bae-Hwan Kim (pp. 743-748).

Ketoprofen (KP) is a widely used non-steroidal anti-inflammatory drug (NSAID). However, an increasing number of case reports suggest that in broad use, KP can cause allergic dermatitis. Most of these adverse effects have been attributed to the photoallergic potential of KP and photosensitivity. With the exception of a few reports in experimental animals, there is little evidence that KP actually causes dermal toxicity. In this study, in order to investigate the eventual underlying causes of KP dermal toxicity, we conducted primary irritation, skin cumulative, skin sensitization, phototoxicity and photosensitization tests in rodents and rabbits. Primary irritation and skin cumulative testing using New Zealand white rabbits revealed that application of KP (22, 15 and 10%) did not induce erythema or edema formation. Moreover, in skin sensitization and skin phototoxicity testing, using Hartley albino guinea pigs, there was no evidence of allergic or phototoxic potential. In the photosensitization test, KP induced skin reactions in six of eight guinea pigs with signs of erythema on the application site. Histologically, in photosensitized skin, epidermal hyperplasia, including incremental stratum granulosum, acanthosis, keratinocyte hypertrophy and dermal inflammatory cell infiltration, was observed. In this animal study, no primary irritation, cumulative irritation, skin sensitization or skin phototoxicity was observed with KP treatment. However, we identified photosensitization as the underlying cause of KP dermal toxicity.

Keywords: Ketoprofen; Dermal toxicity; Primary irritation; Cumulative irritation; Sensitization; Phototoxicity; Photosensitization; Guinea pigs

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Archives of Toxicology (v.81, #10)