Fundamental and Applied Toxicology最新文献

{"title":"Tetracycline-Induced Steatosis in Primary Canine Hepatocyte Cultures","authors":"David E. Amacher ,&nbsp;Barbara-Anne Martin","doi":"10.1006/faat.1997.2389","DOIUrl":"10.1006/faat.1997.2389","url":null,"abstract":"<div><p>Primary hepatocyte cultures prepared from male beagle dog liver were used to determine susceptibility of the canine liver to tetracycline-induced steatosis. The effects of the drug on mitochondrial lipid metabolism and intracellular triglyceride accumulation were monitored at the same time that steatosis was detected by light microscopy and quantitated using lipid-specific stains. Exposure of primary canine hepatocyte cultures to tetracycline for 24–48 h resulted in concentration-dependent, significant increases in the Oil Red O-stained lipid inclusions. Microscopic examination of the total stained areas suggested that increases over control levels were due primarily to the increase in the size of the lipid inclusions rather than in the number. Biochemical analyses for triglyceride content and histological staining with Nile red, another neutral lipid-specific dye, confirmed a specific increase in intracellular triglyceride following a 24-h exposure to noncytotoxic levels of tetracycline. β-oxidation studies based on the oxidation of [¹⁴C]palmitic acid or [¹⁴C]palmitoyl carnitine demonstrated a concentration-dependent inhibition of mitochondrial but not peroxisomal β-oxidation in hepatocytes after a 24-h exposure to tetracycline.<em>In vitro</em>incubation of tetracycline with mitochondria isolated from dog liver showed similar, concentration-dependent inhibition. This study clearly indicates that the canine hepatocyte is susceptible to tetracycline-induced steatosis. Triglyceride accumulation was concomitant with the inhibition of mitochondrial lipid metabolism, indicating that this is a primary mechanism leading to steatosis in dog hepatocytes following tetracycline exposure.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"40 2","pages":"Pages 256-263"},"PeriodicalIF":0.0,"publicationDate":"1997-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2389","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20368299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of the Effects of Musk Ketone on Mouse Hepatic Cytochrome P450 Enzymes","authors":"Sharon B. Stuard,&nbsp;Douglas Caudill,&nbsp;Lois D. Lehman-Mckeeman","doi":"10.1006/faat.1997.2395","DOIUrl":"10.1006/faat.1997.2395","url":null,"abstract":"<div><p>Nitroaromatic musks, including musk ketone (MK; 2,6-dimethyl-3,5-dinitro-4-<em>t</em>-butylacetophenone), are chemicals used as perfume ingredients in household products, cosmetics, and toiletries. Musk xylene (MX; 1,3,5-trinitro-2-<em>t</em>-butylxylene), another nitromusk, is not genotoxic but has been reported to produce mouse liver tumors in a chronic bioassay. In addition, MX has been shown to both induce and inhibit mouse liver cytochrome P450 2B (CYP2B) isozymes. The ability of MX to inhibit CYP2B enzyme activity is attributable to inactivation of the enzyme by a specific amine metabolite. MK is structurally similar to MX, but lacks the nitro substitution that is reduced to the inactivating amine metabolite. Therefore, we hypothesized that MK would induce, but not inhibit, CYP2B isozymes. To test this hypothesis, and to evaluate the effects of MK on mouse liver cytochrome P450 enzymes, two sets of experiments were performed. To evaluate the ability of MK to induce cytochromes P450, mice were dosed daily by oral gavage at dosages ranging from 5 to 500 mg/kg MK for 7 days. This treatment resulted in a pleiotropic response in mouse liver, including increased liver weight, increased total microsomal protein, and centrilobular hepatocellular hypertrophy. At the highest dose tested, MK caused a 28-fold increase in CYP2B enzyme activity and a small (approximately 2-fold) increase in both cytochromes P450 1A and 3A (CYP1A and CYP3A) enzyme activities over control levels. Protein and mRNA analyses confirmed the relative levels of induction for CYP2B, CYP1A, and CYP3A. In addition, the no-observable-effect level (NOEL) for CYP2B induction by MK was 20 mg/kg. To evaluate the ability of MK to inhibit phenobarbital-induced CYP2B activity, mice were given 500 ppm phenobarbital (PB) in the drinking water for 5 days to induce CYP2B isozymes, followed by a single equimolar (0.67 mmol/kg) oral gavage dose of either MK (198 mg/kg) or MX (200 mg/kg), and microsomes were prepared 18 h later. While MX inhibited more than 90% of the PB-induced CYP2B activity in the microsomes, MK caused only a small (about 20%) reduction in PB-induced CYP2B enzyme activity. These results indicate that, like MX, MK is a PB-type inducer of mouse liver CYP2B isozymes, but unlike MX, MK does not effectively inhibit PB-induced CYP2B enzyme activity.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"40 2","pages":"Pages 264-271"},"PeriodicalIF":0.0,"publicationDate":"1997-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2395","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20368300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Index for Volume 40","authors":"","doi":"10.1006/faat.1997.2407","DOIUrl":"https://doi.org/10.1006/faat.1997.2407","url":null,"abstract":"","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"40 2","pages":"Page 272"},"PeriodicalIF":0.0,"publicationDate":"1997-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2407","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"137276290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cumulative Chemical Index for Volumes 35–40","authors":"","doi":"10.1006/faat.1997.2410","DOIUrl":"https://doi.org/10.1006/faat.1997.2410","url":null,"abstract":"","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"40 2","pages":"Pages 290-291"},"PeriodicalIF":0.0,"publicationDate":"1997-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2410","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"137276293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rat Olfactory Mucosa Displays a High Activity in Metabolizing Methyltert-butyl Ether and Other Gasoline Ethers","authors":"Jun-Yan Hong ,&nbsp;Yong-Yu Wang,&nbsp;Flordeliza Y. Bondoc,&nbsp;Chung S. Yang,&nbsp;Maojung Lee,&nbsp;Wei-Qun Huang","doi":"10.1006/faat.1997.2383","DOIUrl":"10.1006/faat.1997.2383","url":null,"abstract":"<div><p>Methyl<em>tert</em>-butyl ether (MTBE) is a widely used gasoline oxygenate. Two other ethers, ethyl<em>tert</em>-butyl ether (ETBE) and<em>tert</em>-amyl methyl ether (TAME), are also used in reformulated gasoline. Inhalation is a major route for human exposure to MTBE and other gasoline ethers. The possible adverse effects of MTBE in humans are a public concern and some of the reported symptoms attributed to MTBE exposure appear to be related to olfactory sensation. In the present study, we have demonstrated that the olfactory mucosa of the male Sprague–Dawley rat possesses the highest microsomal activities, among the tissues examined, in metabolizing MTBE, ETBE, and TAME. The metabolic activity of the olfactory mucosa was 46-fold higher than that of the liver in metabolizing MTBE, and 37- and 25-fold higher, respectively, in metabolizing ETBE and TAME. No detectable activities were found in the microsomes prepared from the lungs, kidneys, and olfactory bulbs of the brain. The observations that the metabolic activity was localized exclusively in the microsomal fraction, depended on the presence of NADPH, and was inhibitable by carbon monoxide are consistent with our recent report on MTBE metabolism in human and mouse livers (Hong<em>et al.,</em>1997) and further confirm that cytochrome P450 enzymes play a critical role in the metabolism of MTBE, ETBE, and TAME. The apparent<em>K_m</em>and<em>V</em>_maxvalues for the metabolism of MTBE, ETBE, and TAME in rat olfactory microsomes were very similar, ranging from 87 to 125 μM and 9.8 to 11.7 nmol/min/mg protein, respectively. Addition of TAME (0.1 to 0.5 mM) into the incubation mixture caused a concentration-dependent inhibition of the metabolism of MTBE and ETBE. Coumarin (50 μM) inhibited the metabolism of these ethers by approximately 87%. Further comparative studies with human nasal tissues on the metabolism of these ethers are needed in order to assess the human relevance of our present findings.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"40 2","pages":"Pages 205-210"},"PeriodicalIF":0.0,"publicationDate":"1997-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2383","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20368293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cumulative Subject Index for Volumes 35–40","authors":"","doi":"10.1006/faat.1997.2409","DOIUrl":"https://doi.org/10.1006/faat.1997.2409","url":null,"abstract":"","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"40 2","pages":"Pages 276-289"},"PeriodicalIF":0.0,"publicationDate":"1997-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2409","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"137276291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subchronic Nasal Toxicity of Hexamethylphosphoramide Administered to Rats Orally for 90 Days","authors":"Douglas A. Keller,&nbsp;Craig E. Marshall,&nbsp;K.P. Lee","doi":"10.1006/faat.1997.2375","DOIUrl":"10.1006/faat.1997.2375","url":null,"abstract":"<div><p>Rats were administered hexamethylphosphoramide (HMPA) at dosages of 10, 100, 300, and 1000 ppm in drinking water or at 15, 40, or 120 mg/kg/day by gavage for approximately 90 days. Another group of rats was implanted subcutaneously with HMPA-filled osmotic minipumps, designed to deliver a dosage of 40 mg/kg/day to prevent the possibility of direct contact of HMPA with the nasal epithelium. After 90 days at 10 ppm in the drinking water, some rats had tracheas lined with regenerated epithelium, but no HMPA-related lesions were present in any other organs and tissues. At 100 ppm, nasal lesions (epithelial denudation, regeneration, and squamous metaplasia) were mostly in the maxilloturbinates, tips of nasoturbinates, and the adjacent septum in the anterior nasal cavity (level I), but the lesions were confined to the ventral region of the mid-anterior nasal cavity (level II) and to recesses of the posterior nasal cavity (levels III and IV). At 300 ppm, nasal turbinates in level I were partially adhered to the nasal septum by fibrous tissue. In level II the lesions were mainly confined to the ventral medial meatus, but were scattered diffusely in levels III and IV. Denuded turbinates showed minimal bone proliferation. At 1000 ppm, the anterior nasal cavity was partially occluded by extensive adhesion of the turbinates to the nasal septum by granulation tissue and proliferating turbinate bone. The general architecture of the posterior nasal cavity was obliterated by the marked proliferation of turbinate bone and fibrous tissue in the interturbinate spaces. Tracheas showed regenerated epithelium and bronchi had focal epithelial denudation at 100, 300, and 1000 ppm. Foamy alveolar macrophages (histiocytosis) were increased in the lungs at 300 and 1000 ppm. Testicular atrophy occurred at 1000 ppm. No other tissues were affected by HMPA treatment. Nasal lesions in rats given HMPA by gavage were identical in nature to, but sometimes slightly more severe than, the lesions in rats given HMPA in the drinking water. Rats given 40 mg/kg/day HMPA via an osmotic minipump had slightly less severe nasal lesions than did the rats given the same dosage of HMPA by gavage. Testicular atrophy was present in the rats given 120 mg/kg/day by gavage. The results of this study show that, with the exception of bone proliferation, systemic delivery of HMPA or its metabolites to the nasal tissue following oral administration causes tissue damage similar to that caused by direct exposure of the nasal tissue via inhalation. Oral administration of HMPA is a less potent route for producing nasal lesions than is inhalation.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"40 1","pages":"Pages 15-29"},"PeriodicalIF":0.0,"publicationDate":"1997-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2375","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20327778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trihalomethane Comparative Toxicity: Acute Renal and Hepatic Toxicity of Chloroform and Bromodichloromethane Following Aqueous Gavage","authors":"Patrick D. Lilly ,&nbsp;Tracey M. Ross ,&nbsp;Rex A. Pegram","doi":"10.1006/faat.1997.2372","DOIUrl":"10.1006/faat.1997.2372","url":null,"abstract":"<div><p>Bromodichloromethane (BDCM) and chloroform (CHCl₃) are by-products of drinking water chlorination and are the two most prevalent trihalomethanes (THMs) in finished drinking water. To date, no comprehensive comparison of the acute renal and hepatic effects of BDCM and CHCl₃following oral gavage in an aqueous dosing vehicle has been conducted. To characterize BDCM- and CHCl₃-induced nephro- and hepatotoxicity following aqueous gavage and compare directly the responses between these THMs, 95-day-old male F-344 rats were given single oral doses of 0.0, 0.75, 1.0, 1.5, 2.0, or 3.0 mmol BDCM or CHCl₃/kg body wt in an aqueous 10% Emulphor solution. Compound-related hepatic and renal damage was evaluated by quantitating clinical toxicity markers in the serum and urine, respectively. Both THMs appear to be equally hepatotoxic after 24 h, but BDCM caused significantly greater elevations in serum hepatotoxicity markers than CHCl₃at 48 h following exposure to 2.0 and 3.0 mmol/kg. In addition to causing more persistent liver toxicity than CHCl₃, BDCM also appears to be slightly more toxic to the kidney at lower doses. Potency differences between the two THMs may be due to pharmacokinetic dissimilarities such as greater metabolism of BDCM to reactive metabolites or more extensive partitioning of BDCM into kidneys and fat depots, resulting in prolonged target tissue exposure.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"40 1","pages":"Pages 101-110"},"PeriodicalIF":0.0,"publicationDate":"1997-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2372","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20328283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repeated Independent Exposures to Domoic Acid Do Not Enhance Symptomatic Toxicity in Outbred or Seizure-Sensitive Inbred Mice","authors":"Yong G. Peng ,&nbsp;Edwin C. Clayton ,&nbsp;Larry W. Means ,&nbsp;John S. Ramsdell","doi":"10.1006/faat.1997.2360","DOIUrl":"10.1006/faat.1997.2360","url":null,"abstract":"<div><p>Domoic acid (DA) is an environmental neurotoxin to humans. This work examines whether repeated exposure to subsymptomatic or symptomatic nonlethal doses of domoic acid leads to enhanced symptomatic toxicity in ICR outbred and DBA inbred strains of laboratory mice. A multiple independent exposure paradigm was designed in which doses were administered intraperitoneally every other day for 7 days to achieve four separate exposures to domoic acid. We first examined the effect of repeated exposure on serum clearance of domoic acid. Serum domoic acid levels did not differ following a single or repeated exposure. We next examined the effect of repeated exposure on symptomatic toxicity. The mean toxicity scores did not show a significant difference between single and repeated exposures of either subsymptomatic (0.5 mg/kg) or symptomatic sublethal (2.0 mg/kg) doses of domoic acid. We then examined the effects of repeated domoic acid exposure on a second strain of mouse. DBA mice were chosen based upon their sensitivity to kainic acid-induced seizures; however, the ICR mice were more sensitive to low-dose domoic acid toxicity, particularly in terms of onset and duration of stereotypic scratching behavior. Our results indicate that both strains of mice have comparable concentration-dependent toxic responses to domoic acid; however, differences exist in the magnitude of the response and in specific symptoms. The mean toxicity scores did not show a significant difference when a single exposure (1.0 and 2.0 mg/kg domoic acid) and repeated exposure of the same dose were compared in the DBA mice. This study provides no evidence that short-term repeated exposure to domoic acid in laboratory mice alters domoic acid clearance from the serum, or leads to a more sensitive or a greater neurotoxic response.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"40 1","pages":"Pages 63-67"},"PeriodicalIF":0.0,"publicationDate":"1997-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2360","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20328279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lack of Embryotoxicity of Fumonisin B1in New Zealand White Rabbits","authors":"James B. LaBorde ,&nbsp;Ketti K. Terry ,&nbsp;Paul C. Howard ,&nbsp;James J. Chen ,&nbsp;Thomas F.X. Collins ,&nbsp;Mary E. Shackelford ,&nbsp;Deborah K. Hansen","doi":"10.1006/faat.1997.2380","DOIUrl":"10.1006/faat.1997.2380","url":null,"abstract":"<div><p>Fumonisin B₁(FB₁) is one of a number of mycotoxins produced by fungi, especially<em>Fusarium</em>sp. As a contaminant of many maize-derived products, this toxin is associated with a variety of animal diseases, including esophageal cancer and possibly neural tube defects in humans. We have investigated the embryotoxic potential of this compound in New Zealand White rabbits. Animals were dosed by gavage daily on GD 3–19 with purified FB₁at 0.10, 0.50, or 1.00 mg/kg/day. Maternal lethality occurred at the 0.50 and 1.00 mg/kg/day doses. When examined on GD 29, there were no differences in maternal body weight, maternal weight gain, maternal organ weights, number of nonlive implantations, and number of malformations. Fetal weight was decreased at 0.50 and 1.00 mg/kg/day (13 and 16%, respectively); this was true for male and female pups. Fetal liver and kidney weights were also decreased at these doses. Analysis of embryonic sphinganine to sphingosine ratios demonstrated no differences between control and treated embryos on GD 20, although these ratios were increased in maternal urine, serum, and kidney when compared to control animals. These data suggest that FB₁did not cross the placenta and that the observed decreased fetal weight was probably the result of maternal toxicity, rather than any developmental toxicity produced by FB₁.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"40 1","pages":"Pages 120-128"},"PeriodicalIF":0.0,"publicationDate":"1997-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2380","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20328285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}