The genotoxic and cytotoxic effects of ribavirin in rat bone marrow

The genotoxic and cytotoxic effects of the antiviral drug, ribavirin, was studied in rat bone marrow by employing the micronucleus assay. Ribavirin in doses of 10, 15, 20, 30, 50, 75, 100 and 200 mg/kg, and cyclophosphamide (CP) 40 mg/kg (only for sex-difference study) were injected intraperitoneally. Bone marrow was collected at 24 h and 48 h following the injection. To evaluate the recovery, the bone marrow was also sampled at 72 h from 20, 100 and 200 mg/kg treated rats. The micronucleus assay was conducted according to the standard procedure. Ribavirin elevated the incidence of micronuclei (except 10 mg/kg) in erythrocytes (P<0.01). The micronucleated polychromatic erythrocytes showed the initial steep increase at 15 and 20 mg/kg dose level, then with the gradual increase, possibly due to the limited metabolism and action of higher doses. The incidence of micronucleated normochromatic erythrocytes was not dose dependent. The effect was more at 48 h than 24 h due to prolonged toxicity of the drug or its metabolites, and by 72 h, recovery was observed eventhough the genotoxicity was significant. The PCE% decreased as the dose was increased up to 75 mg/kg, then without much difference between two higher doses. Only 100 mg/kg ribavirin and CP showed more toxicity on male rats. Cytotoxicity was seen due to hindered erythropoiesis or cell destruction. Our findings suggest that ribavirin is genotoxic and cytotoxic agent for rat bone marrow.     

Evaluation of hyperdiploidy in the bladder epithelial cells of male F344 rats treated with ortho-phenylphenol

Ortho-phenylphenol (OPP) is a broad-spectrum fungicide and anti-bacterial agent that has been shown to cause bladder cancer in male F344 rats. An earlier study to investigate the potential role of aneuploidy in OPP-induced bladder carcinogenicity, failed to detect increases in frequencies of hyperdiploidy/polyploidy in treated animals, presumably due to the presence of polyploid cells in the bladder. To overcome this problem, we utilized a novel approach to determine increases in numerical alterations in the slowly dividing replicating cells of the rat bladder following treatment with OPP. Collagenase digestion of the bladder was used to enrich for actively-dividing cells and FISH in conjunction with BrdU was employed to detect hyperdiploidy in the replicating interphase cells. Initial studies were performed using FISH with a chromosome 4 probe. Follow-up studies were conducted with OPP and a positive control, vinblastine sulfate using probes for chromosomes 4 and 19. No significant increases in hyperdiploidy/polyploidy were seen in the replicating bladder cells of the OPP-treated rats using FISH with either the chromosome 4 or 19 probes. As expected, no significant increases in hyperdiploidy were seen in the non-replicating cells. In contrast, highly significant increases in hyperdiploidy/polyploidy, as detected using FISH with probes for either chromosome 4 or 19, were seen in the replicating cells from rats treated with a combination of OPP and vinblastine. The inability to detect increases in hyperdiploidy/polyploidy in the bladder of OPP-treated rats indicates that chromosome gain is unlikely to play a major role in the early genotoxic effects of OPP. However, the increase in hyperdiploidy/polyploidy induced by vinblastine sulfate in OPP-treated rats, clearly demonstrates that this approach using FISH in combination with BrdU is capable of detecting changes in chromosome number even in slowly-dividing tissues, such as the urinary bladder.     

Relationship between body iron stores and diquat toxicity in male Fischer-344 rats

The effects of body iron stores on diquat (DQ)-induced toxicity were examined in male Fischer-344 rats, which are sensitive to this herbicide. The rats (5 weeks old) were fed diets containing 40 (lower iron storage [LIS] group) or 320 ppm iron (higher iron storage [HIS] group) for 5 weeks. The concentrations of nonheme iron and ferritin in the liver and kidney were significantly higher in the HIS group than in the LIS group (P<0.0001), although there was no significant differences between the HIS and LIS groups in hematological parameters, including red blood cell count, hemoglobin concentration, and mean corpuscular volume. Three hours after administration of 0.1 mmol DQ/kg, serum alanine aminotransferase and urea nitrogen were significantly higher than in controls (saline injection) for both the LIS and HIS groups (P<0.01), and, after DQ injection, these parameters were significantly higher in the HIS group than in the LIS group (P<0.01). When the rats were injected with 0.075 or 0.1 mmol DQ/kg, the survival time was significantly shorter in the HIS group than in the LIS group (P<0.05). These findings suggest that higher body iron stores result in more severe DQ toxicity in Fischer-344 rats.     

Safety and toxicological evaluation of Rhizopora mucronata (a mangrove from Vellar estuary,India): assessment of mutagenicity,genotoxicity and in vivo acute toxicity

The present was carried out to evaluate the toxicity of methanolic leaf extract of Rhizophora mucronata (MERM) under in vivo and in vitro conditions. Mutagenicity of MERM (up to 4,000 μg/plate) evaluated by Salmonella/microsome assay (TA98, TA100, TA1535 and TA1538 strains), with or without metabolic activation showed no mutagenic effect in any of the tester strain. Evaluation of genotoxicity (comet assay) and cytotoxicity in PBMC revealed that MERM showed no significant difference in comet tail moment (TM) and tail scores and cytotoxicity up to 24 h respectively. In acute toxicity studies, oral administration of single doses of MERM (250–2,000 mg/kg) in Wistar rats produced neither mortality nor any noticeable changes in behavior. Hematological and biochemical parameters showed no difference, except for a significant increase in ALT and AST at the highest dose. Histopathological findings revealed hepatotoxicity and neurotoxicity at highest dose of extract. In subacute toxicity studies administration of MERM (1,000 mg/kg) for 28 consecutive days neither altered the body weight gain nor behavioral parameters. No significant change was observed in the hematological and biochemical parameters analyzed. Histopathological examination showed normal architecture suggesting no morphological disturbances. Collectively, these data demonstrate that consumption of MERM for various medicinal purpose is safe.     

Interactive intoxicating and ameliorating effects of tannic acid,aluminum (Al3+), copper (Cu2+), and selenate (SeO42−) in wheat roots: a descriptive and mathematical assessment

Tannic acids and tannins are produced by plants and are important components of soil and water organic matter. These polyphenolic compounds form complexes with proteins, metals and soil particulate matter and perform several physiological and ecological functions. The tannic acid (TA) used in our study was a mixture of gallic acid and galloyl glucoses ranging up to nonagalloyl glucose. TA inhibited root elongation in wheat seedlings (Triticum aestivum L. cv. Scout 66) at concentrations >4 mg l^?1; but TA alleviated the toxicity of Al³⁺, Cu²⁺ and SeO₄^2?; and Al³⁺ and SeO₄^2? alleviated the toxicity of TA. The interactions of Al³⁺ and TA (each toxic but each alleviating the toxicity of the other) were stoichiometric. Growth was affected as though 1 kg TA bound 2.76 mol Al so strongly that if (mol Al)/(kg TA) <2.76, then free Al ≈ 0, and if (mol Al)/(kg TA) >2.76, then free TA ≈ 0. This stoichiometry is consistent with one mole of galloyl groups binding approximately 0.5 mol Al. Using this binding scheme, growth was modeled successfully on the basis of free TA and free Al. TA enhanced the negativity of root surfaces and enhanced the binding of Al and Cu there without enhancing their toxicity. These and other interactions among TA, Al³⁺, Cu²⁺, SeO₄^2?, Ca²⁺, Na⁺ and H⁺ were quantified with a comprehensive non‐linear equation with statistically significant coefficients.     

Long-Term Exposure to [Cr3O(O2CCH2CH3)6(H2O)3]+ in Wistar Rats Fed Normal or High-Fat Diets Does Not Alter Glucose Metabolism

The essentiality of chromium(III) has been the subject of much debate, particularly in healthy subjects. Chromium(III)-containing supplements are widely used for body mass loss, building of lean muscle mass, and improving glucose and lipid metabolism. [Cr₃O(O₂CCH₂CH₃)₆(H₂O)₃]⁺, Cr3, is one of the most-studied chromium nutritional supplements. The current study evaluates the effects of long-term (15 months) supplementation with Cr3 on body mass and glucose metabolism in Wistar rats on traditional and cafeteria-style (high fat, high carbohydrate) diets. Male Wistar rats were randomly assigned to one of four treatment groups: (1) control diet (milled Harlan Teklad LM-485 rodent diet), (2) control diet?+?1 mg Cr3/kg body mass/day, (3) a cafeteria-style (CAF) diet (high fat, high carbohydrate), or (4) CAF diet?+?1 mg Cr3/kg/day. Cr3 supplementation had no effect on fasting blood glucose levels or blood glucose levels in response to glucose and insulin challenges. Rats consuming the CAF?+?Cr3 diet tended to have a significantly higher body mass than rats consuming the CAF diet, but necropsy results showed no difference in visceral fat or body wall thickness between groups. These data suggest that long-term Cr3 supplementation does not significantly affect body mass in rats consuming a normal diet or glucose levels or metabolism in rats consuming either diet.     

Importance of Molar Ratios in Selenium-Dependent Protection Against Methylmercury Toxicity

The influence of dietary selenium (Se) on mercury (Hg) toxicity was studied in weanling male Long Evans rats. Rats were fed AIN-93G-based low-Se torula yeast diets or diets augmented with sodium selenite to attain adequate- or rich-Se levels (0.1, 1.0 or 15 μmol/kg, respectively) These diets were prepared with no added methylmercury (MeHg) or with moderate- or high-MeHg (0.2, 10 or 60 μmol/kg, respectively). Health and weights were monitored weekly. By the end of the 9-week study, MeHg toxicity had impaired growth of rats fed high-MeHg, low-Se diets by approximately 24% (p < 0.05) compared to the controls. Growth of rats fed high-MeHg, adequate-Se diets was impaired by approximately 8% (p < 0.05) relative to their control group, but rats fed high-MeHg, rich-Se diets did not show any growth impairment. Low-MeHg exposure did not affect rat growth at any dietary Se level. Concentrations of Hg in hair and blood reflected dietary MeHg exposure, but Hg toxicity was more directly related to the Hg to Se ratios. Results support the hypothesis that Hg-dependent sequestration of Se is a primary mechanism of Hg toxicity. Therefore, Hg to Se molar ratios provide a more reliable and comprehensive criteria for evaluating risks associated with MeHg exposure.     

Macromolecular covalent binding of [14C]nitrobenzene in the erythrocyte and spleen of rats and mice

Nitrobenzene exposure is known to produce red blood cell damage as well as engorgement and sinusoidal congestion of the spleen in male Fischer-344 (F-344) rats but not in male B6C3F1 mice. These studies were conducted to investigate the species differences in the covalent binding of [¹⁴C]nitrobenzene in the erythrocyte and spleen and to assess the contribution of nitrobenzene-induced erythrocytic damage to the splenic effects. Total and covalently bound ¹⁴C concentrations in erythrocytes of rats were 6–13 times greater than those of mice following a single oral dose of 75, 150, 200 or 300 mg/kg [¹⁴C]nitrobenzene, suggesting that species differences in nitrobenzene-induced red blood cell toxicity may be related to differences in erythrocytic accumulation of nitrobenzene and its metabolites. Covalently bound ¹⁴C in erythrocytes of rats peaked 24 h following administration of 200 mg [¹⁴C]nitrobenzene/kg; in contrast, bound radio-label in erythrocytes from mice plateaued at 10 h. Splenic engorgement increased in a time-related manner in treated rats but not in mice. Species specificity was also observed in the accumulation of bound radiolabel in the spleen. Gel filtration and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of lysed, dialyzed erythrocytes from treated rats revealed that hemoglobin was the primary, if not the exclusive, site of macromolecular covalent binding following nitrobenzene treatment. SDS-PAGE of dialyzed rat spleens revealed that 82% of total bound ¹⁴C migrated identically to hemoglobin. These data indicate that covalent binding of [¹⁴C]nitrobenzene and its metabolites in the spleen is primarily derived from bound ¹⁴C from scavenged erythrocytes. Therefore, the species differences in splenic engorgement and accumulation of [¹⁴C]nitrobenzene may be related to differences in susceptibility to nitrobenzene-induced red blood cell damage.     

Subcutaneous administration of bovine superoxide dismutase protects lungs from radiation-induced lung injury

Abstract

Background. The objective of the present study was to determine whether single administration of the antioxidant enzyme bovine superoxide dismutase (bSOD) after radiation therapy (RT) mitigates development of pulmonary toxicity in rats. Methods. Female F344 rats (n = 60) were divided among six experimental groups: (1) RT, single dose of 21 Gy to the right hemithorax; (2) RT + 5 mg/kg bSOD; (3) RT + 15 mg/kg bSOD; (4) No RT; (5) sham RT + 5 mg/kg bSOD; and (6) sham RT + 15 mg/kg bSOD. A single subcutaneous injection of bSOD (5 or 15 mg/kg) was administered 24 h post-radiation. The effects of bSOD on radiation-induced lung injury were assessed by measurement of body weight, breathing frequency, and histopathological changes. Immunohistochemistry was used to evaluate oxidative stress (8-OHdG⁺, NOX4⁺, nitrotyrosine⁺, and 4HNE⁺ cells), macrophage activation (ED1⁺), and expression of profibrotic transforming growth factor-β or TGF-β in irradiated tissue. Results. Radiation led to an increase in all the evaluated parameters. Treatment with 15 mg/kg bSOD significantly decreased levels of all the evaluated parameters including tissue damage and breathing frequency starting 6 weeks post-radiation. Animals treated with 5 mg/kg bSOD trended toward a suppression of radiation-induced lung damage but did not reach statistical significance. Conclusions. The single application of bSOD (15 mg/kg) ameliorates radiation-induced lung injury through suppression of reactive oxygen species/reactive nitrogen species or ROS/RNS-dependent tissue damage.     

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on lipid profiles in tissue of the Fischer rat

Female Fischer 344 rats were given single oral doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 10, 50 or 100 μg/kg, and sacrificed 1, 3, 10, 14 or 21 days later. The fatty livers caused by a sub-lethal dose of TCDD involved a temporary increase in triglyceride and free fatty acid levels, with a persistent decrease in levels of sterol esters. In contrast, the fatty livers resulting from a lethal dose of TCDD involved a large increase in cholesterol esters and free fatty acids, with little change in triglyceride levels. These changes appeared to result in part from damage sustained by lysosomes. TCDD also altered the lipoprotein composition of the serum, the fatty acid composition of various lipid classes in liver and serum, and the ultrastructure of the liver (formation of myeloid bodies). A rapid, dose-dependent effect of TCDD, was the elevation of levels of organic-soluble fluorescent pigment in the heart. This pigment was found to match a previously characterized fraction of lipofuscins in fluorescence spectrum and chromatographic properties. The relationship of these observations to a possible mechanism of toxicity for TCDD involving radical-induced lipid peroxidation is discussed.     

Mutagenicity of vinyl chloride,chloroethyleneoxide, chloroacetaldehyde and chloroethanol

Exposure of S. typhimurium strains TA 1530, TA 1535 and G-46 to vinyl chloride increased the number of his⁺ rev./plate 16, 12 or 5 times over the spontaneous mutation rate. The mutagenic response for TA 1530 strain was enhanced 7, 4 or 5-fold when fortified S-9 liver fractions from humans, rats or mice were added. In TA 1530 strain, chloroacetic acid showed only toxic effects, while chloroacetaldehyde, chloroethanol and chloroethyleneoxide caused a mutagenic response. The latter compound was shown to be a strong alkylating agent.     

Speciation and metabolism of selenium injected with 82Se-enriched selenite and selenate in rats

Selenate and selenite injected intravenously into rats were speciated by the HPLC–ICP MS method with use of an enriched stable isotope as the tracer. In dose–relation experiments, ⁸²Se-enriched selenate or selenite was injected intravenously into male Wistar rats of 8 weeks of age (three rats/group) at single doses of 10, 25, 50, 100 and 200 μg/kg body weight for the selenate group, and 2, 5, 10, 25 and 50 μg/kg body weight for the selenite group. The animals were sacrificed 1 or 24 h later, and the concentrations and distributions of ⁸²Se in the liver, kidneys, serum, and urine remaining in the bladder or 24-h urine were determined. In time-course experiments, ⁸²Se-enriched selenate and selenite were injected at doses of 50 and 10 μg/kg body weight, respectively, and the animals were sacrificed 5, 15, 30, 60 and 180 min later. It was suggested that selenate is directly taken up by the liver with an efficiency of approximately 1/2 compared with selenite, the latter being taken up by the liver after being metabolized to selenide in red blood cells. Although selenate and selenite were metabolized differently in the bloodstream, and also a part of only selenate was excreted directly into the urine, the ⁸²Se taken up by the liver was shown to be metabolized in a manner indistinguishable between selenate and selenite. ⁸²Se of selenite origin but not of selenate origin was suggested to undergo redox reaction in the bloodstream. These results suggest that although parenteral selenate is utilized less efficiently by the body, it is utilized in the liver in a similar manner to selenite much more safely.     

In vivo genotoxicity of ortho-phenylphenol, biphenyl, and thiabendazole detected in multiple mouse organs by the alkaline single cell gel electrophoresis assay

In Japan, ortho-phenylphenol (OPP), biphenyl (BP), and thiabendazole (2-(4'-thiazolyl)benzimidazole, TBZ) are commonly used as a postharvest treatment to preserve imported citrus fruits during transport and storage. We used a modification of the alkaline single cell gel electrophoresis (SCG) (Comet) assay to test the in vivo genotoxicity of those agents in mouse stomach, liver, kidney, bladder, lung, brain, and bone marrow. CD-1 male mice were sacrificed 3, 8, and 24 h after oral administration of the test compounds. OPP (2000 mg/kg) induced DNA damage in the stomach, liver, kidney, bladder, and lung, BP (2000 mg/kg) and TBZ (200 mg/kg) induced DNA damage in all the organs studied. For OPP, increased DNA damage peaked at 3–8 h and tended to decrease at 24 h. For BP, on the contrary, increased DNA migration peaked at 24 h. That delay may have been due to the fact that OPP is metabolized by cytochrome 450 and prostaglandin H synthase to phenylbenzoquinone (PBQ), a DNA binding metabolite, and BP is metabolized to PBQ via OPP and m-phenylphenol. The positive response to TBZ, an aneugen, supports the in vivo DNA-damaging action of TBZ.     

1H NMR Spectroscopic and Histopathological Studies on Propyleneimine-Induced Renal Papillary Necrosis in the Rat and the Multimammate Desert Mouse (Mastomys natalensis)

The renal papillary toxin, propyleneimine (PI), was administered at 20 or 30 μl/kg i.p. to male Sprague Dawley (SD) rats (n = 5), Fischer 344 (F344) rats (n = 4), and to multimammate desert mice (Mastomys natalensis, n = 4). Urine was collected at time points up to 4 days p.d. and the toxicological response of the different animal models to PI compared using ¹H NMR spectroscopy of urine, renal histopathology, and urinary assays for alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and γ-glutamyl transpeptidase (γGT). The renal papillae of both F344 and SD rats showed extensive necrotic lesions 4 days post-dosing and in some cases sloughing of the papilla. However, only slight renal papillary necrosis (RPN) was observed in Mastomys treated with 20 μl/kg PI and, although slight to moderate damage was observed at 30 μl/kg, PI-treated Mastomys showed substantially less RPN than either group of PI-treated rats. ¹H NMR urinalysis showed that PI treatment caused a decrease in the urinary concentrations of succinate (0–24 hr p.d.) and citrate (24–48 hr p.d.) and an increase in creatine (0–48 hr p.d.) in all animal models. Trimethylamine-N-oxide (24–48 hr) and 2-oxoglutarate concentrations decreased initially following the administration of PI and then rose above control levels. The ¹H NMR-detected urinary biochemical effects of PI in all three models were similar. However, taurine concentrations were elevated in the urine of Mastomys following PI treatment, perhaps indicating a degree of liver damage, whereas taurinuria was not seen in either SD or F344 rats. These observations are discussed in relation to the potential mechanism of PI-toxicity.     

Amine-free melanin-concentrating hormone receptor 1 antagonists: Novel non-basic 1-(2H-indazole-5-yl)pyridin-2(1H)-one derivatives and mitigation of mutagenicity in Ames test

To develop non-basic melanin-concentrating hormone receptor 1 (MCHR1) antagonists with a high probability of target selectivity and therapeutic window, we explored neutral bicyclic motifs that could replace the previously reported imidazo[1,2-a]pyridine or 1H-benzimidazole motif. The results indicated that the binding affinity of a chemically neutral 2H-indazole derivative 8a with MCHR1 (hMCHR1: IC₅₀ = 35 nM) was comparable to that of the imidazopyridine and benzimidazole derivatives (1 and 2, respectively) reported so far. However, 8a was positive in the Ames test using TA1537 in S9− condition. Based on a putative intercalation of 8a with DNA, we introduced a sterically-hindering cyclopropyl group on the indazole ring to decrease planarity, which led to the discovery of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-{[5-(trifluoromethyl)thiophen-3-yl]methoxy}pyridin-2(1H)-one 8l without mutagenicity in TA1537. Compound 8l exerted significant antiobesity effects in diet-induced obese F344 rats and exhibited promising safety profile.     

Maternal-fetal distribution and prenatal toxicity of 2,2,4-trimethyl-1,2-dihydroquinoline in the rat

BACKGROUND: Polnoks R (poly‐2,2,4‐trimethyl‐1,2‐dihydroquinoline) is used as an antioxidant in elastomer processing. It is an embryotoxic and fetotoxic agent. This chemical given per os to female rats induces also teratogenic effect but only at doses toxic to the mother. The aim of the study was to evaluate prenatal development and tissue distribution in rats exposed to 2,2,4‐trimethyl‐1,2‐dihydroquinoline (TMDHQ), a monomer of Polnoks R. METHODS: Females were exposed orally to unlabeled TMDHQ during organogenesis at doses 50–400 mg/kg to asses prenatal toxicity and to radiolabeled ¹⁴C monomer at a dose 210 mg/kg to evaluate tissues distribution. RESULTS: TMDHQ administered to pregnant females per os at doses 100 mg/kg and higher produced teratogenic effect (cleft palate, wavy ribs, kyphoscoliosis, exencephaly, external hydrocephalus, hydronephrosis, and renal hypoplasia). Peak ¹⁴C‐radioactivity was found in mothers' plasma about 10 hr after administration of this compound at dose 210 mg/kg. The accretion of ¹⁴C proceeded with a kinetic constant of 0.35 hr ^?1 and a half‐life of 53.3 hr. Kidneys are the main organs of monomer excretion. The highest concentration of ¹⁴C in maternal tissues 24 hr after oral dosing was found in adipose tissue, sciatic nerve, muscles, kidneys, and liver. Radiocarbon retention in fetuses was the highest in kidneys at all time points after dosing. CONCLUSIONS: This study has demonstrated that transplacental exposure to Polnoks R monomer is teratogenic in rats. ¹⁴C retention in placenta, amniotic fluid, and fetal tissues indicates that this compound or its metabolites penetrate into placenta to the fetus. Birth Defects Res B 68:375–382, 2003. © 2003 Wiley‐Liss, Inc.     

Genetic differences in Δ9-tetrahydrocannabinol-induced facilitation of brain stimulation reward as measured by a rate-frequency curve-shift electrical brain stimulation paradigm in three different rat strains

Lewis, Fischer 344, and Sprague-Dawley rats were implanted with electrodes in the medial forebrain bundle and trained to lever press for brain stimulation reward using a ratefrequency curve-shift electrical brain stimulation paradigm based on a series of 16 pulse frequencies ranging from 25 to 141 Hz in descending order. Once reward thresholds were stable, rats were given 1.0 mg/kg Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the psychoactive constituent in marijuana and hashish, or vehicle, by intraperitoneal injection. Lewis rats showed the most pronounced Δ⁹-THC-induced enhancement of brain reward functions. Sprague-Dawley rats showed an enhancement of brain reward functions that was approximately half that seen in Lewis rats. Brain reward functions in Fischer 344 rats were unaffected by Δ⁹-THC at the dose tested. These results are consistent with previous work showing Lewis rats to be highly sensitive to the rewarding properties of a variety of drugs of abuse, including opiates, cocaine, and alcohol, while Fischer 344 rats are relatively less sensitive. They extend such previous findings to cannabinoids, and further suggest that genetic variations to other cannabinoid effects may also exist.     

Consequence of aflatoxin B1 ingestion on the membrane-bound liver endoplasmic reticulum Ca2+-ATPase of protein-undernourished Fischer F344 rats

Ingestion of the mycotoxin Aflatoxin B₁ (AFB₁) by protein-undernourished Fischer F344 rats for twelve weeks resulted in significant (p<0.05) increases in the proliferation of liver cells, reduced body weight and increased microsomal Ca²⁺-ATPase activity. Cyt. P₄₅₀ content, -Glutamyl Transferase (GGT) and Glutathione Transferase (GST) activities were unaffected. The ingestion of AFB₁ by normal rats had no effect on all the parameters investigated. It appears that the microsomal Ca²⁺-pumping ATPase of Protein-Undernourished (PU) Fischer F344 rats is more sensitive to the mycotoxin AFB₁ than its counterpart in well-nourished rats. The use of PU rat as animal model for studies on AFB₁ toxicity, particularly the effect of AFB₁ on the regulation of intracellular calcium ion concentration ([Ca²⁺]_i), is suggested.