Inhibition of Human Plasma and Serum Butyrylcholinesterase (EC 3.1.1.8) by {alpha}-Chaconine and {alpha}-Solanine

The purpose of these experiments was to determine the reversibilityof -chaconine and -solanine inhibition of human plasma butyrylcholinesterase(BuChE). For the substrate -naphthylacetate, optimal assay conditionswere 0.50 M sodium phosphate buffer and a substrate concentrationof 3–5 ' 10^–4 M. Dibucaine (1 ' 10^–5 M) indicatedthe usual phenotype for all subjects; -chaconine and -solanineat 2.88 ' 10^–6 M inhibited BuChE about 70 and 50%, respectively.One-and 24-hr incubations at 1 ' 10^–1 M with -chaconine,-solanine, paraoxon, eserine, and ethanol yielded reversibleinhibition with dilution except for paraoxon. Twenty-four-hourdialyses of incubations showed no inhibition except for paraoxon.PAGE enzyme activity gels of 1-and 24-hr incubations also showedno inhibition except for paraoxon. -Chaconine and -solanineare reversible inhibitors of human butyrylcholinesterase. Atestimated tissue levels, -chaconine, -solanine, and solanidineinhibited BuChE 10–86%. In assays which combined -chaconine,-solanine, and solanidine, inhibition of BuChE was less thanadditive. No inhibition of albumin -naphthylacetate esterase(an arylesterase) was noted with any inhibitor. The importanceof these data to adverse toxicological effects of potato alkaloidsis discussed.     

The Perturbation of Hepatic Glutathione by {alpha}2-Adrenergic Agonists

The Perturbation of Hepatic Glutathione by ₂ -Adrenergic Agonists.James, Robert C, Roberts, Stephen M. and Harbison, Raymond D.(1983). Fundam. Appl. Toxicol.. 3: 303–308. Single injectionsof epinephrine significantly lowered the hepatocellular levelsof reduced glutathione (GSH) while producing small but significantelevations in serum glutamic-pyruvic transaminase (SGPT) activity.Hormones, i.e. glucagon and the corticosteroids, were also foundto depress significantly hepatic glutathione. Based upon theagonist-antagonist studies performed, the hepatic GSH loweringeffects of epinephrine appear to be mediated solely by ₂ receptors.Adrenergic antagonists with ₂ receptor blocking properties,phenotolamine and yohimbine, prevented the epinephrine-inducedlowering of GSH while agonists with ₂ activity, clonidine andguanabenz, mimicked epinephrine's response. Antagonists witheither ₁or ß activity, i.e. prazosin, phenoxybenzamineand propranolol, did not prevent the epinephrine-induced loweringof hepatic GSH. Contrary to these findings antagonists witheither or P receptor blocking activity significantly reducedthe epinephrine-induced elevations in SGPT activity. Thus, therewas no apparent relationship between the elevation of SGPT activityand the reduction in hepatic glutathione levels. It is concludedthat the therapeutic administration of these compounds, or physiologicresponses to stress or pain, may exacerbate the hepatotoxicityof compounds detoxified by GSH or alter important glutathione-mediatedhepatocellular processes.     

The Effects of 10 Triterpenoid Compounds on Experimental Liver Injury in Mice

The purpose of this study was to compare the hepatoprotec tiveeffects of 10 oleanane-type triterpenoid compounds on threeknown hepatotoxicants in mice. These compounds in clude oleanolicacid, ursolic acid, uvaol, -hederin (-H), heder agenin, glycyrrhizin,18-glycyrrhetinic acid (-GA), 18ß-glycyrrhetinic acid(ß-GA), 19-hydroxyl asiatic acid 28-O-ß-D-glucoside (HAG), and 19-hydroxyl asiatic acid (HA). They wereadministrated sc for 3 days at 200 µmol/kg, except for-H, which was given at 100 , imol/kg for 2 days. Acute liverinjury was produced in male CF-1 mice by CCI (15 µl/kg,ip), acetaminophen (500 mg/kg, ip), and cadmium chloride (3.7mg/kg, iv). Liver damage was assessed by serum activities ofalanine aminotransferase and sorbitol dehydrogenase, as wellas by his topathological examination. -Hedenn, ursolic acid,and olean olic acid markedly decreased the toxicity producedby all three hepatotoxicants. Uvaol significantly decreasedCd and Cd- induced hepatotoxicity, but had no effect on acetaminophentox icity. Glycyrrhizin, -GA, and ß-GA decreased acetaminopheninduced liver injury, whereas hederagenin, HAG, and HA did notprotect against any of the hepatotoxicants. In addition, -hederin,ursolic acid, oleanolic acid, and uvaol increased hepatic metallothioneinlevels by 87-, 48-, 28-, and 1 0-fold, respectively, as determinedby the Cd/hemoglobin assay. In conclusion, among the 10 triterpenoidcompounds examined, -hederin, ur solic acid, and oleanolic acidappear to be the most effective in protecting against CCl_4-acetaminophen-, and Cd-induced liver injury.     

Increased Hyaline Droplet Formation in Male Rats Exposed to Decalin Is Dependent on the Presence of {alpha}2u-Globulin

Increased Hyaline Droplet Formation in Male Rats Exposed toDecalin Is Dependent on the Presence of _2u-Globulin. RIDDER,G. M., VON BARGEN, E. C., ALDEN, C. L., AND PARKER, R. D. (1990).Fundam. Appl. Toxicol. 15, 732–743. A peculiar decalin-inducedmale rat nephropathy associated with the altered renal handlingof filtered protein appears limited to the accumulation of theprotein, _2u-globulin. Several strains of male rats that produce_2u-globulin (Fischer-344, Sprague-Dawley, Buffalo, and NorwayBrown) demonstrate spontaneous renal cortical hyaline dropletswhich are exacerbated after exposure to decalin. In all cases,a close correlation exists between hyaline droplet formationobserved histologically and _2u-globulin accumulation measuredbiochemically. In stark contrast, the NCI-Black-Reiter strain,which does not produce measurable quantities of _2u-globulin,neither forms hyaline droplets nor accumulates any filteredprotein in its kidney cortex either spontaneously or after exposureto decalin. Also, female rats injected ip with male rat _2u-globulinexhibit increased hyaline droplet formation and _2u-globulinaccumulation when treated with decalin. These data provide evidencethat the presence of _2u-globulin is key in understanding whythis nephropathy appears unique to the male rat.     

NCI-Black-Reiter (NBR) Male Rats Fail to Develop Renal Disease following Exposure to Agents That Induce {alpha}-2u-Globulin ({alpha}2u) Nephropathy

NCI-Black-Reiler (NBR) Male Rats Fail to Develop Renal Diseasefollowing Exposure to Agents That Induce _2u-Globulin (_2u) Nephropathy.Dietrich, D. R., and Swenberg, J. A. (1991). Fundam. Appl. Toxicol16, 749–762. The NCI-Black-Reiter (NBR) rat is the onlystrain of male rat known not to synthesize the hepatic formof the low molecular weight protein, _2u-globulin. In previousstudies, NBR rats were shown not to develop renal disease whenexposed to decalin, a compound known to induce _2u-globulin nephropathyin other rat strains. The objective of this study was to showthat the presence of _2u-globulin (_2u-) is essential for thedevelopment of this syndrome in rats exposed to 2,2,4-trimethylpentane(TMP), 1,4-dichlorobenzene (DCB), isopho-rone (IP), PS-6 unleadedgasoline (UG), and d-limonene (d-L). The induction of _2u-nephropathyin F344 male rats with lindane was used as a positive controland this response was contrasted to male NBR and female F344rats treated with lindane. Five to seven 11-week-old male NBRrats were exposed to TMP (500 mg/kg/day), DCB (500 mg/kg/day),IP (1000 mg/kg/day), UG (500 mg/kg/day), d-L (1650 mg/kg/day),or lindane (10 mg/kg/day) and five 11-week-old male and femaleF344 rats were exposed to lindane (10 mg/kg/day) by oral gavageon 4 consecutive days. NBR male and F344 male and female ratsgavaged with corn oil were incorporated in the study as vehiclecontrols. The presence of hyaline droplets was assessed in perfusion-fixedkidneys by staining paraffin sections with Mallory-Heidenheinstain and in GMA sections with Lee's methylene basic blue fuchsinstain. Paraffin sections were also analyzed immunohistochemicallyfor the presence of _2u-. Under exposure conditions that clearlyinduce _2u-nephropathy in male F344 rats, no lesions, hyalinedroplets, or _2u- were detectable in treated or control maleNBR and female F344 rats. It is thus concluded that the presenceof _2u is causal to the development of renal disease in ratsexposed to TMP, DCB, IP, UG, d-L, and lindane.     

d-Limonene Induced Hyaline Droplet Nephropathy in {alpha}2u-Globulin Transgenic Mice

d-Limonene is a hyaline droplet inducing agent and producesnephrotoxicity in male rats when the 1,2-epoxide metabolitebinds to 2u-globulin. Mice, which do not synthesize 2u-globulin,are resistant to hyaline droplet nephropathy. In this study,the ability of d-limonene to cause hyaline droplet nephropathyin a transgenic mouse engineered to express 2u-globulin wasevaluated. The C57BL/6-derived mice excreted 0.4 ± 0.1mg 2u-globulin/day, or approximately 16 mg 2u-globulin/kg bodywt. This represents about 30% of the amount excreted by adultmale rats (11.9 ± 1.1 mg/day or approximately 48 mg/kg).Transgenic mice excreted less mouse urinary protein (9.3 ±1.2 mg/day) than normal mice (15.1 ± 1.6 mg/day). Unlikenormal male rats, untreated transgenic mice did not show significantspontaneous hyaline droplet formation. Liver microsomes fromnaive transgenic mice oxidized d-limonene to the cis- and trans-isomersof the 1,2-epoxide, and following oral treatment with [¹⁴C]d-limonenereversible binding of d-limonene equivalents to renal cytosolicproteins was observed. Furthermore, with d-limonene treatment,hyaline droplets were observed in the transgenic mouse kidneys.These droplets, however, were much smaller in size than thoseseen in d-limonene-treated male rats. The accumulation of 2u-globulinin the kidneys of transgenic mice and normal male rats beforeand after d-limonene treatment was analyzed by Western blotting.These results indicated that 2u-globulin was present in thekidneys of the control transgenic mice, despite the lack ofspontaneous hyaline droplet formation. After d-limonene treatment,approximately a three fold increase in 2u-globulin in the transgenicmouse kidney was observed, a response similar in magnitude tothat seen in d-limonene-treated male rats. These results indicatethat expression of 2u-globulin in a species that does not normallydevelop hyaline droplet nephropathy is necessary and sufficientto render that species sensitive to this renal toxicity.     

Application of Molecular Encapsulation for Toxicology Studies: Comparative Toxicity of p-Chloro-{alpha},{alpha},{alpha}-trifluorotoluene in {alpha}-Cyclodextrin Vehicle versus Corn Oil Vehicle in Male and Female Fischer 344 Rats and B6C3F1 Mice

The application of -cyclodextrin (-CD) as an alternative vehiclefor water insoluble and volatile chemicals was investigatedin toxicity studies of p-chloro-,,-trifluorotoluene (CTFT).Groups of F344 rats and B6C3F1 mice of each sex were administeredCTFT (97% pure) by gavage in either corn oil or -CD aqueousformulations daily for 14 consecutive days. The dose levelsused were 10 (mice only), 50, 400, and 1000 mg/kg for corn oilvehicle and 10, 50, and 400 mg/kg (maximum achievable dose atgavage volume of 5 ml/kg) for -CD vehicle. With both vehiclesCTFT and a_2u-globulin were found to accumulate in the male ratkidney after 14 days of exposure and a dose-related toxic nephropathywas observed at dose of 50 mg/kg or higher. The hepatocellularhypertrophy and cytoplasmic vacuolation of the adrenal cortexwhich appeared in dosed male and female rats were also foundto be independent of vehicle. Clinical pathology findings suggesteda mild anemia and cholestasis in rats. With both vehicles notissue bioaccumulation of CTFT was found in male or female mice.Vehicle-independent hepatocellular hypertrophy and cholestasiswere also observed in mice at doses of 400 and 1000 mg/kg. Inconclusion, the -CD vehicle does not affect the toxic responsesof CTFT in both sexes of both species. The results of the studiessuggest that -CD may be an appropriate alternative vehicle fortoxicity studies.     

Organ-Specific Hematopoietic Changes Induced by a Recombinant Human Interferon-{alpha} in Mice

Organ-Specific Hematopoietic Changes Induced by a RecombinantHuman Interferon- in Mice. ROSENTHAL, G. J., STRANAHAN, R. P.,ILL, THOMPSON, M., BLAIR, P., GERMOLEC, D. R., COMMENT, C. E.,SCHWAB, K., AND LUSTER, M. I. (1990). Fundam. Appl. Toxicol.14, 666–675. Interferon-a (IFN-) is a naturally occurringcytokine that mediates numerous biological activities and hasdemonstrated therapeutic potential in a variety of malignancies.Encouraging activity against HIV-1 replication has also beenobserved with IFN- in the treatment of AIDS, although hematotoxicityhas been a frequently observed side effect. In addition, invitro studies have suggested that IFN- may function as a down-regulatorof myelopoiesis. A recombinant hybrid of subtypes of human IFN-,rHuIFN-A/D, has antiviral activity in mu-rine cells in vitroand In vivo. This study examines the effect of acute and subchronicexposure to rHuIFN-A/D on hemopoietic and immune parametersin C57B1/6 mice. IFN-a was administered ip at 0, 1000, 10,000,and 100,000 units/day for either 1 or 10 consecutive days. Manyof the known effects of IFN- in humans such as anemia, leukopenia,and thrombocytopenia were observed in mice following subchronicexposure, with the latter two effects also manifested followingacute exposure. Further analysis showed that this leukopeniawas not selective. Both splenic and bone marrow cells were examinedfollowing 10 days of dosing with the high dose of IFN-. Lymphocyteswere reduced in both compartments, while granulocytes were increasedin both compartments. Bone marrow cells programmed to differentiateinto granulocytes (CFU-G) were suppressed, while macrophageprogenitors (CFU-M) were stimulated. Erythroid cells decreasedin the marrow but increased in the spleen, suggesting that themicroenvironmerit may play a significant role in the effectof IFN-. The proliferative capacity of both B and T spleniclymphocytes was significantly suppressed in a dose-related fashionfollowing multiple exposure to IFN-a. Clinically, IFN-a is mostoften given in multiple doses and the present data suggest thatsuch a regimen is toxic to both erythroid and myeloid cells,as well as being immunotoxic to splenic B and T lymphocytes.     

Manganese Induces Dopaminergic Neurodegeneration via Microglial Activation in a Rat Model of Manganism

Manganese is an essential trace element required for normaldevelopment and bodily functions. However, exposure of the brainto excessive amounts of manganese results in neurotoxicity.Although previous studies examining manganese neurotoxicityhave focused on neuronal injury, especially direct injury todopaminergic neurons, the effects of manganese-induced neurotoxicityon glial cells have not been reported. The current study wasdesigned to examine the effect of manganese on microglial activation,and the underlying mechanism of manganese-induced dopaminergicneuronal injury in vivo. We established an animal model of manganismby intrastriatal injection of MnCl₂·4H₂O into male Sprague-Dawleyrats. One day after administration of manganese, a few microglialcells in the substantia nigra (SN) were activated, althoughthe number of tyrosine hydroxylase (TH)–immunoreactiveneurons in the SN was unaffected. Seven days after administrationof manganese, a marked reduction in the number of TH-immunoreactiveneurons was observed in the SN, and the majority of microglialcells were activated. We found that manganese upregulated induciblenitric oxide synthase (iNOS) and tumor necrosis factor (TNF-)gene expression, as well as iNOS, TNF-, and interleukin-1β(IL-1β) protein levels in the SN. Furthermore, treatmentwith minocycline, an inhibitor of microglial activation, attenuatedmicroglial activation and mitigated IL-1β, TNF-, and iNOSproduction as well as dopaminergic neurotoxicity induced bymanganese. These results suggested that dopaminergic neuronscould be damaged by manganese neurotoxicity, and that the activatedmicroglial cells and their associated activation products playedan important role in this neurodegenerative process.     

Technical Grade but Not Recrystallized {alpha}-Naphthylthiourea Potentiates Superoxide Release by Rat Neutrophils Stimulated in Vitro by Phorbol Myristate Acetate

Technical Grade but Not Recrystallized -Naphthylthiourea PotentiatesSuperoxide Release by Rat Neutrophils Stimulated in VitrobyPhorbol Myristate Acetate. ROTH, R.A., AND BALL, T.M. (1986).Fundam. Appl. Toxicol. 7, 324–328. -Naphthylthiourea (ANTU)causes pulmonary edema and pleural effusion in rats. It hasbeen suggested that ANTU pneumotoxicity may be mediated by bloodneutrophils (PMNs) via the release of reactive oxygen species.Accordingly, we tested the effect of technical grade ANTU (tANTU)on the ability of rat peritoneal PMNs to release superoxide(O₂). tANTU did not itself stimulate O₂ production by PMNs,but it increased the O₂ released in response to PMN stimulationby phorbol myristate acetate (PMA). This effect was dependentupon the amount of tANTU added. In PMNs activated in vitro bya submaximal PMA stimulus, addition of 20 µg/ml tANTUdoubled superoxide release. When tANTU was recrystallized fromethanol, the purified ANTU was not effective in potentiatingthe effect of PMA on PMNs. This suggests that an impurity intechnical grade ANTU is capable of increasing O₂ release bystimulated PMNs. tANTU and recrystallized ANTU caused similarpneumotoxicity in rats in vivo, suggesting that the unidentifiedimpurity does not markedly influence the biologic effects ofANTU.     

Pharmacokinetic Fate of14C-Labeled Deoxynivalenol in Swine

Pharmacokinetic Fate of ¹⁴C-Labeled Deoxynivalenol in Swine.PRELUSKY, D. B., HARTIN, K. E., TRENHOLM, H. L., AND MILLER,J. D. (1988). Fundam. Appl Toxicol. 10,276-286. The pharmacokineticsof the trichothecene mycotoxin deoxynivalenol (DON) was investigatedin swine following intravenous (0.30 mg, 0.35 µCi/kg)and intragastric (0.60 mg, 0.60 µCi/kg) administrationof the ¹⁴C-labeled toxin. After iv dosing, plasma concentrationdata favored a three-compartment open model with half-life valuesfor the rapid distribution (), slower distribution (ß),and terminal elimination () phases of 5.8, 96.7, and 510.0 min,respectively. The apparent volume of distribution (V') was 1.34liter/kg, the volume of the central compartment (K_c) was 0.166liter/kg, and the plasma clearance was 1.81 ml/min/kg. DON wasrapidly cleared essentially unchanged (>95%), and was excretedprimarily in unne (86–104%), with minor elimination inbile (3–5%). Following intragastric dosing DON was veryrapidly absorbed, reaching near peak plasma levels within 15–30min. Levels remained elevated (63-325 ng/ml) for approximately9 hr, and began declining slowly (t ß= 7.1 hr) thereafter.The calculated systemic bioavailability (F) was between 48 and65%, although urinary and biliary recoveries indicated marginallygreater absorption actually occurred (54–85%). Overall,although DON was eliminated rapidly and completely within 24hr following a single iv or intragastric dose, data suggestthat residues may undergo temporary sequestration in a tissuedepot.     

Modulation of Pulmonary Eicosanoid Metabolism following Exposure to Sulfuric Acid

Modulation of Pulmonary Eicosanoid Metabolism following Exposureto Sulfuric Acid. SCHLESINGER, R. B., GUNNISON, A. F., AND ZELIKOFF,J. T. (1990). Fundam. Appl. Toxicol. 15, 151–162. Eicosanoids(arachidonic acid metabolites) are potent biological mediators.Modulation of their metabolism by air pollutants may be a possiblefactor in the pathogenesis of environmentally related lung disease.Sulfuric acid (H₂SO₄) aerosols are components of ambient airin many areas. Rabbits were exposed to H₂SO₄ (0.3 µm)at 250, 500, or 1000 µg/m³ for 1 hr/ day for 5 days. Theywere then euthanized, the lungs lavaged, and eicosanoid analysesperformed by radioimmunoassay of acellular lavage fluid. Anexposure-concentration-dependent decrease in levels of prostaglandinsE₂ and F₂ and thromboxane B₂ was found; no change in leukotrieneB₄ was observed. Tracheal explants exposed to acidic environmentsin vitro also showed reduced production of PGE₂, PGF₂, and TxB₂.Incubation with sodium sulfate (Na₂SO₄ showed no effect of thesulfate ion (SO₄^2–). This study, the first to examineeicosanoid production after in vivo exposure to pure H₂SO₄ droplets,indicates that such exposure can modulate arachidonic acid metabolism,and that this is likely due to the deposition of hydrogen ion(H⁺ on target issue.     

Trans, Trans-2,4-Decadienal, a Product Found in Cooking Oil Fumes, Induces Cell Proliferation and Cytokine Production Due to Reactive Oxygen Species in Human Bronchial Epithelial Cells

Dienaldehydes are by-products of peroxidation of polyunsaturatedlipids and commonly found in many foods or food-products. BothNational Cancer Institute (NCI) and NTP have expressed greatconcern on the potential genotoxicity and carcinogenicity ofdienaldehydes. Trans, trans-2,4-decadienal (tt-DDE or 2,4-De),a specific type of dienaldehyde, is abundant in heated oilsand has been associated with lung adenocarcinoma developmentin women due to their exposure to oil fumes during cooking.Cultured human bronchial epithelial cells (BEAS-2B cells) wereexposed to 0.1 or 1.0 µM tt-DDE for 45 days, and oxidativestress, reactive oxygen species (ROS) production, GSH/GSSG ratio,cell proliferation, and expression of TNF and IL-1ßwere measured. The results show that tt-DDE induced oxidativestress, an increase in ROS production, and a decrease in GSH/GSSGratio (glutathione status) in a dose-dependent manner. Treatmentof BEAS-2B cells with 1.0 µM tt-DDE for 45 days increasedcell proliferation and the expression and release of pro-inflammatorycytokines TNF and IL-1ß. Cotreatment of BEAS-2B cellswith antioxidant N-acetylcysteine prevented tt-DDE-induced cellproliferation and release of cytokines. Therefore, these resultssuggest that tt-DDE-induced changes may be due to increasedROS production and enhanced oxidative stress. Since increasedcell proliferation and the release of TNF- and IL-1ßare believed to be involved in tumor promotion, our resultssuggest that tt-DDE may play a role in cancer promotion. Previousstudies on dienaldehydes have focused on their genotoxic orcarcinogenic effects in the gastrointestinal tract; the presentstudy suggests a potential new role of tt-DDE as a tumor promoterin human lung epithelial cells.     

Development of Fish Peritoneal Macrophages as a Model for Higher Vertebrates in Immunotoxicological Studies: I. Characterization of Trout Macrophage Morphological, Functional, and Biochemical Properties

Development of Fish Peritoneal Macrophages as a Model for HigherVertebrates in Immunotoxicological Studies. I. Characterizationof Trout Macrophage Morphological, Functional, and BiochemicalProperties. ZELIKOFF, J. T., ENANE, N. A., BOWSER, D., SQUIBB,K. S., AND FRENKEL, K. (1991). Fundam. Appl. Toxicol. 16, 576–589.The immune defense mechanisms of fish are not as well characterizedas those of mammals but seem to be related and similarly competent.Because of this, there is an increased interest in the immuneresponses of fish as models for higher vertebrates in immunotoxicologicalstudies. Prior to such studies, baseline criteria for specificcomponents of the immune response needed to be established.For this study, we have examined trout macrophage morphologyusing light and scanning electron microscopy, phagocytic activity,random and stimulus-directed migration, and superoxide anionradical (^{dot}) production for resident and lipopolysacharide (LPS) or Aeromonas salmonicidae-elicited rainbowtrout (Oncorhynchus mykiss) peritoneal macrophages (M). Followingperitoneal lavage, >89% of the cells were M as determinedby differential counts and nonspecific esterase staining. Immunizationwith LPS and A. salmonicidae increased M number {small tilde}5and 13-fold, respectively, and overall size. Trout M were phagocyticallyactive engulfing serum opsonized latex particles and were mobile,migrating both randomly and in a directed fashion towards formyl-methionine-L-leucine-L-phenylalanine(FMLP) and trout serum-derived complement fragment C5a. Concentrationsof FMLP (100 nM) and C5a (0.01–1%) effective for attractingtrout M are the same as those used to attract rabbit M. Residenttrout M produced negligable quantities of-(^{dot}) following stimulation with 1 µg/ml phorbol myristate acetate;Aeromonas-elicited M produced (^{dot}) in a time-dependen manner which peaked after 60 min at 2.9 nmolper 2 ? 10₅ cells and then declined. The results of this studyprovide a data base for future toxicological studies with troutperitoneal M and indicate the usefulness of this system forimmunotoxicological studies.     

Experimental T-2 Toxicosis in Swine: I. Changes in Cardiac Output, Aortic Mean Pressure, Catecholamines, 6-Keto-PGF1{alpha}, Thromboxane B2, and Acid-Base Parameters

Experimental T-2 Toxicosis in Swine. I. Changes in Cardiac Output,Aortic Mean Pressure, Catecholamines, 6-Keto-PGF₁, ThromboxaneB₂, and Acid-Base Parameters. LORENZANA, R. M., BEASLEY, V.R., BUCK, W. B., GHENT, A. W., LUNDEEN, G. R., AND POPPENGA,R. H. (1985). Fundam. Appl. Toxicol.. 5,879-892. T-2 toxin givenas a single intravascular dose to swine produced a shock syndrome.Dosages of 0.6 or 4.8 mg/kg were administered to different groupsof swine. Shock was characterized by reductions in cardiac outputand blood pressure, and increased plasma concentrations of epinephrine,norepinephrine, thromboxane B₂, 6-keto PGF₁, and lactate. Totalperipheral resistance was unchanged in the high-dose group butdecreased in the low-dose group. Pulmonary vascular resistanceincreased in both groups. Decreases occurred in arterial pHand arterial oxygen partial pressure. No alterations occurredin plasma concentrations of histamine or serotonin.     

Comparative Skin Phototoxicity in Mice with Two Photosensitizing Drugs: Benzoporphyrin Derivative Monoacid Ring A and Porfimer Sodium (Photofrin)

Benzoporphyrin derivative monoacid ring A (BPD-MA) and Photofrin(porfimer sodium) are photodynamic anticancer agents. The chemicalstructures of the two regioisomers of BPD-MA are 9-methyl trans-{±)-18-ethenyl-4,4-dihydro-3,4-bis(methoxycarbonyl)-4,8,14,19-tetramethyl-4,4-dihydro-3,4-bis (methoxycarbonyl)-4, 8,14,19-tetramethyl-23H, 25H-benzo(b)porphine-9,13-dipropanoateand 13-methyl-trans-(±)-18-ethenyl-4,4-dihydro-3,4-bis(methoxycarbonyl)-4,8,14,19-tetramethyl-23H,25H-benzo(b)porphine-9,13-dipropanoate.Photofrin (a registered trademark of American Cyanamid Co.)is a polyporphrin oligomer containing ester and ether linkages.The ability of BPD-MA or Photofrin to cause skin phototoxicitywas investigated in mice exposed to simulated sunlight (light)3, 24, or 48 hr after receiving a single intravenous injectionof vehicle or 2, 10, or 20 mg/kg of BPD-MA or Photofrin. Thedata were from two studies conducted using male and female CD1mice (7 weeks old). The hair of the dorsal thoracic area wasclipped 24 hr prior to exposure to light. Mice were exposedto light for 5 min. The clipped area of skin was the primarysite for the evaluation of phototoxicity. Mice were observedfor 2 weeks after treatment. There were no significant findingsin controls or in mice given 2 mg/kg of BPD-MA. When mice wereexposed to light 3 hr after dosing, both BPD-MA (10 or 20 mg/kg)and Photofrin (2, 10 or 20 mg/kg) caused phototoxicity. Deathoccurred in all mice given 20 mg/kg of BPD-MA or Photofrin,and in the majority of mice given 10 mg/kg of Photofrin. Insurviving mice, the skin of the back reacted by forming a largearea of eschar (scab). When mice were exposed to light 24 or48 hr after administration of BPD-MA or Photofrin, significantphototoxicity (browned skin and eschar formation) was observedonly in the mice given Photofrin. The data suggest that in miceBPD-MA causes substantial tissue injury when photoactivated3 hr after administration, but that the potential for phototoxicityis essentially gone after 24 hr. In contrast, phototoxicitywas elicited in the skin of mice exposed to simulated sunlight3, 24, and 48 hr after injection of Photofrin.