ABSTRACT
Malignant neuroendocrine tumors were diagnosed in the stomach of two out of sixty female Sprague-Dawley rats treated for 89 weeks with a high dose of a novel, small molecule, cannabinoid-1 antagonist. The tumors were associated with parietal cell atrophy accompanied by foveolar hyperplasia of the glandular stomach mucosa. Parietal cell atrophy/foveolar hyperplasia was considered test article related at the high dose, given the higher incidence and severity relative to untreated controls, although the precise mechanism of the parietal cell atrophy was undetermined. Spontaneous gastric neuroendocrine tumors are very rare in rats, and the current cases were considered secondary to parietal cell atrophy causing reduced gastric acid secretion and subsequent overstimulation of gastrin release through a feedback loop.
Subject(s)
Neuroendocrine Tumors , Stomach Neoplasms , Animals , Atrophy/chemically induced , Atrophy/complications , Atrophy/pathology , Female , Gastric Mucosa/pathology , Hyperplasia/pathology , Neuroendocrine Tumors/chemically induced , Neuroendocrine Tumors/complications , Neuroendocrine Tumors/pathology , Parietal Cells, Gastric/pathology , Rats , Rats, Sprague-Dawley , Stomach Neoplasms/etiology , Stomach Neoplasms/pathologyABSTRACT
COVID-19 is a potentially fatal infection caused by the SARS-CoV-2 virus. The SARS-CoV-2 3CL protease (Mpro) is a viral enzyme essential for replication and is the target for nirmatrelvir. Paxlovid (nirmatrelvir co-administered with the pharmacokinetic enhancer ritonavir) showed efficacy in COVID-19 patients at high risk of progressing to hospitalization and/or death. Nonclinical safety studies with nirmatrelvir are essential in informing benefit-risk of Paxlovid and were conducted to support clinical development. In vivo safety pharmacology assessments included a nervous system/pulmonary study in rats and a cardiovascular study in telemetered monkeys. Potential toxicities were assessed in repeat dose studies of up to 1 month in rats and monkeys. Nirmatrelvir administration (1,000 mg/kg, p.o.) to male rats produced transient increases in locomotor activity and respiratory rate but did not affect behavioral endpoints in the functional observational battery. Cardiovascular effects in monkeys were limited to transient increases in blood pressure and decreases in heart rate, observed only at the highest dose tested (75 mg/kg per dose b.i.d; p.o.). Nirmatrelvir did not prolong QTc-interval or induce arrhythmias. There were no adverse findings in repeat dose toxicity studies up to 1 month in rats (up to 1,000 mg/kg daily, p.o.) or monkeys (up to 600 mg/kg daily, p.o.). Nonadverse, reversible clinical pathology findings without clinical or microscopic correlates included prolonged coagulation times at ≥60 mg/kg in rats and increases in transaminases at 600 mg/kg in monkeys. The safety pharmacology and nonclinical toxicity profiles of nirmatrelvir support clinical development and use of Paxlovid for treatment of COVID-19.
Subject(s)
Antiviral Agents , COVID-19 Drug Treatment , Animals , Antiviral Agents/adverse effects , Male , RatsABSTRACT
We report histopathology of retinal myelination discovered in a cynomolgus monkey. It consisted of a uniform population of spindle cells arranged in fascicles within the retina at the optic disk. The present case is remarkable in that there is a paucity of reports describing myelinated retinal nerve fibers in monkeys.
Subject(s)
Choristoma/pathology , Macaca fascicularis , Monkey Diseases/pathology , Nerve Fibers, Myelinated/pathology , Retina/pathology , Animals , MaleABSTRACT
The present article describes an occurrence of testicular microlithiasis in a cynomolgus monkey from a routine regulatory toxicology study. The monkey was from a negative control group. Microscopically, the lesion was characterized by multiple extracellular mineralized calculi within seminiferous tubular epithelia of both testes without any tissue reaction or abnormal condition such as cryptorchidism, testicular neoplasm, or hypogonadism. The present case is remarkable in that there is a paucity of reports on spontaneous testicular microlithiasis in nonhuman primates. It is hoped that this case report will help to facilitate the differentiation of spontaneous changes from induced changes in nonhuman primate toxicology studies that are designed to use limited numbers of animals.
ABSTRACT
Drug-induced phospholipidosis is characterized by intracellular accumulation of phospholipids with lamellar bodies in cells exposed to xenobiotics. Demonstration of the lamellar bodies by transmission electron microscopy (TEM) is the hallmark for a definitive diagnosis of phospholipidosis. However, the preparation of tissue samples for TEM and their ultrastructural evaluation are technically challenging and time consuming. Paraphenylenediamine (PPD) is essentially a fat stain, and the staining mechanism is based upon the osmication of unsaturated lipids. Thus, the application of PPD staining to osmicated tissue samples is considered an optimal way to identify lipids. We evaluated the potential of PPD staining to localize phospholipid accumulations on osmium-fixed semi-thin tissue sections of the lung, kidney, and liver, which were affected with phospholipidosis, under a light microscope. PPD staining revealed the presence of PPD positive dark fine granular material in the cytoplasm for all affected tissues examined, which correlated ultrastructurally with lamellar bodies as well as a light microscopic finding of cytoplasmic vacuolation. The great advantage of PPD is that it can be incorporated into the protocol for standard TEM tissue preparation and significantly improve the efficiency of TEM work. In conclusion, PPD provides a simple, sensitive, and reliable method for visualizing phospholipid accumulation on light microscopy and represents an easy tool to study drug-induced phospholipidosis.
Subject(s)
Kidney/metabolism , Lipidoses/diagnosis , Liver/metabolism , Lung/metabolism , Phenylenediamines/chemistry , Phospholipids/metabolism , Animals , Kidney/ultrastructure , Lipidoses/metabolism , Liver/ultrastructure , Lung/ultrastructure , Macaca fascicularis , Microscopy , Microscopy, Electron, Transmission , Rats, Sprague-Dawley , Staining and LabelingABSTRACT
The female reproductive cycle is orchestrated by cyclical and coordinated hormonal changes under the direction of the hypothalamic-pituitary-gonadal (HPG) axis. Any disruption of the HPG axis may lead to functional and structural alterations in the female reproductive system. Test article-related disturbances in the estrous cycle can be recognized in nonclinical toxicity studies by staging the cycle based on microscopic evaluation of female reproductive organs. In chronic rat toxicity studies, an additional complication is the development of reproductive senescence, which is associated with natural alterations in the reproductive cycle leading to changes in the female reproductive system that can potentially be confused with test article effects. The current article describes the features of persistent estrus, one stage of reproductive senescence, in middle-aged Sprague-Dawley rats and discusses elements to help differentiate senescence from induced effects.
Subject(s)
Estrus/drug effects , Histocytochemistry/methods , Hypothalamo-Hypophyseal System/drug effects , Ovary/drug effects , Reproduction/drug effects , Xenobiotics/pharmacology , Animals , Female , Ovary/pathology , Rats , Rats, Sprague-Dawley , Toxicity TestsABSTRACT
Glucokinase activators (GKAs) are being developed for the treatment of type 2 diabetes. The toxicity of 4 GKAs (PF-04279405, PF-04651887, piragliatin, and PF-04937319) was assessed in mice, rats, dogs, and/or monkeys. GKAs were administered for 2 to 8 weeks. Standard endpoints, glucose, and insulin were assessed. All compounds produced varying degrees of hypoglycemia in all species. Brain neuronal necrosis and/or peripheral neuropathy were observed with most compounds. These findings are consistent with literature reports linking hypoglycemia with nervous system effects. Arteriopathy, mainly of cardiac vessels, was observed at a low frequency in monkey and/or dog. Arteriopathy occurred only at doses that produced severe and prolonged periods of repeated hypoglycemia. Since this lesion occurred in multiple studies with structurally distinct GKAs, these results suggested arteriopathy was related to GKA pharmacology. The morphological characteristics of the arteriopathy were consistent with that produced by experimental catecholamine administration. We hypothesize that the prolonged periods of hypoglycemia resulted in increased local and/or systemic concentrations of catecholamines via a counterregulatory and/or stress-related mechanism. Alternatively, prolonged hypoglycemia may have resulted in endothelial dysfunction leading to arteriopathy. This risk can be managed in human patients in clinical studies by careful glucose monitoring and intervention to avoid prolonged episodes of hypoglycemia.
Subject(s)
Azetidines/adverse effects , Benzeneacetamides/adverse effects , Benzofurans/adverse effects , Hypoglycemia/pathology , Necrosis/pathology , Peripheral Nervous System Diseases/pathology , Pyrimidines/adverse effects , Animals , Azetidines/blood , Benzeneacetamides/blood , Benzofurans/blood , Chromatography, High Pressure Liquid , Dogs , Drug Evaluation, Preclinical , Female , Hypoglycemia/chemically induced , Hypoglycemic Agents/adverse effects , Insulin/blood , Macaca fascicularis , Male , Mice , Mice, Inbred ICR , Necrosis/chemically induced , Neurons/drug effects , Neurons/pathology , Peripheral Nervous System Diseases/chemically induced , Pyrimidines/blood , Rats , Rats, Sprague-DawleyABSTRACT
Comparative nonclinical studies were conducted with the proposed biosimilar PF-05280586 and rituximab-EU (MabThera®). In side-by-side analyses, peptide maps and complement-dependent cytotoxicity assay results were similar. Sexually-mature cynomolgus monkeys were administered PF-05280586 or rituximab-EU as a single dose of 0, 2, 10, or 20 mg/kg on day 1 and observed for 92 days (single-dose study) or as 5 weekly injections of 0 or 20 mg/kg and necropsied on day 30, the day after the 5th dose, or on day 121 (repeat-dose study). The pharmacokinetic and pharmacodynamic profiles for both molecules were similar. Marked depletion of peripheral blood B cells 4 days after dosing was followed by near or complete repletion (single-dose study) or partial repletion (repeat-dose study). In the single-dose study, anti-drug antibodies (ADA) were detected by day 29 in all animals administered PF-05280586 or rituximab-EU and persisted through day 85, the last day tested. In the repeat-dose study, ADA were detected on day 121 in 50% of animals administered PF-05280586 or rituximab-EU. Both molecules were well tolerated at all doses. In all endpoints evaluated, PF-05280586 exhibited similarity to rituximab-EU.
Subject(s)
Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antibodies, Monoclonal, Murine-Derived/pharmacokinetics , Animals , Antigens, CD20/metabolism , B-Lymphocytes/drug effects , B-Lymphocytes/metabolism , Biosimilar Pharmaceuticals/administration & dosage , Biosimilar Pharmaceuticals/pharmacology , Dose-Response Relationship, Drug , Endpoint Determination , Female , Macaca fascicularis , Male , Reproducibility of Results , RituximabABSTRACT
The degradation tag (dTAG) system for target protein degradation can remove proteins from biological systems without the drawbacks of some genetic methods, such as slow kinetics, lack of reversibility, low specificity, and the inability to titrate dosage. These drawbacks can make it difficult to compare toxicity resulting from genetic and pharmacological interventions, especially in vivo. Because the dTAG system has not been studied extensively in vivo, we explored the use of this system to study the physiological sequalae resulting from CDK2 or CDK5 degradation in adult mice. Mice with homozygous knock-in of the dTAG sequence onto CDK2 and CDK5 were born at Mendelian ratios despite decreased CDK2 or CDK5 protein levels in comparison with wild-type mice. In bone marrow cells and duodenum organoids derived from these mice, treatment with the dTAG degrader dTAG-13 resulted in rapid and robust protein degradation but caused no appreciable change in viability or the transcriptome. Repeated delivery of dTAG-13 in vivo for toxicity studies proved challenging; we explored multiple formulations in an effort to maximize degradation while minimizing formulation-related toxicity. Degradation of CDK2 or CDK5 in all organs except the brain, where dTAG-13 likely did not cross the blood brain barrier, only caused microscopic changes in the testis of CDK2dTAG mice. These findings were corroborated with conditional CDK2 knockout in adult mice. Our results suggest that the dTAG system can provide robust protein degradation in vivo and that loss of CDK2 or CDK5 in adult mice causes no previously unknown phenotypes.
Subject(s)
Cyclin-Dependent Kinase 5 , Proteins , Male , Mice , Animals , Cyclin-Dependent Kinase 5/genetics , Cyclin-Dependent Kinase 5/metabolism , Proteins/metabolism , ProteolysisABSTRACT
The present article describes an unusual proliferative islet finding observed incidentally in a young male Wistar rat in a 2-week toxicity study. Histologically, the islet lesion was characterized by diffuse enlargement of the islets, which consisted of peripheral proliferation of non-insulin-containing islet cells surrounding normal-appearing insulin-containing cells in the center. To the authors' knowledge, this is the first report of spontaneous proliferative islet lesion composed of non-insulin-containing cells in young rats.
Subject(s)
Hyperplasia/pathology , Islets of Langerhans/pathology , 2-Hydroxypropyl-beta-cyclodextrin , Animals , Blood Glucose , Cell Proliferation , Female , Injections, Subcutaneous , Insulin/blood , Islets of Langerhans/cytology , Male , Plasma/chemistry , Rats , Rats, Wistar , beta-Cyclodextrins/administration & dosageABSTRACT
COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.
Subject(s)
COVID-19 Drug Treatment , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus Protease Inhibitors/administration & dosage , Indoles/administration & dosage , Leucine/administration & dosage , Pyrrolidinones/administration & dosage , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacokinetics , Alanine/administration & dosage , Alanine/adverse effects , Alanine/analogs & derivatives , Alanine/pharmacokinetics , Animals , COVID-19/virology , Chlorocebus aethiops , Coronavirus 229E, Human/drug effects , Coronavirus 229E, Human/enzymology , Coronavirus Protease Inhibitors/adverse effects , Coronavirus Protease Inhibitors/pharmacokinetics , Disease Models, Animal , Drug Design , Drug Synergism , Drug Therapy, Combination , HeLa Cells , Humans , Indoles/adverse effects , Indoles/pharmacokinetics , Infusions, Intravenous , Leucine/adverse effects , Leucine/pharmacokinetics , Mice , Pyrrolidinones/adverse effects , Pyrrolidinones/pharmacokinetics , Severe acute respiratory syndrome-related coronavirus/drug effects , Severe acute respiratory syndrome-related coronavirus/enzymology , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Vero CellsABSTRACT
COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. The designed phosphate prodrug PF-07304814 is metabolized to PF-00835321 which is a potent inhibitor in vitro of the coronavirus family 3CL pro, with selectivity over human host protease targets. Furthermore, PF-00835231 exhibits potent in vitro antiviral activity against SARS-CoV-2 as a single agent and it is additive/synergistic in combination with remdesivir. We present the ADME, safety, in vitro , and in vivo antiviral activity data that supports the clinical evaluation of this compound as a potential COVID-19 treatment.
ABSTRACT
Anomalies of renal development comprise abnormalities in the amount of renal tissue (agenesis and hypoplasia); anomalies of renal position, form, and orientation; and renal dysplasia. There are previous reports of canine renal dysplasia in different breeds but none in the Beagle breed. This is the first report of renal dysplasia in this breed of dog. Morphologic descriptions of the range of microscopic features observed in four cases of renal dysplasia from preclinical studies in laboratory Beagle dogs are presented (including persistent primitive mesenchyme, persistence of metanephric ducts, asynchronous differentiation of nephrons, and atypical tubular epithelium), along with a basis for the classification of the lesion.
Subject(s)
Dog Diseases/pathology , Kidney Diseases/veterinary , Kidney/abnormalities , Animals , Dog Diseases/genetics , Dogs , Female , Kidney Diseases/genetics , Kidney Diseases/pathology , Kidney Failure, Chronic/genetics , Kidney Failure, Chronic/pathology , Kidney Failure, Chronic/veterinary , MaleABSTRACT
Acetyl-CoA carboxylase (ACC) catalyses the first step of de novo lipogenesis (DNL). Pharmacologic inhibition of ACC has been of interest for therapeutic intervention in a wide range of diseases. We demonstrate here that ACC and DNL are essential for platelet production in humans and monkeys, but in not rodents or dogs. During clinical evaluation of a systemically distributed ACC inhibitor, unexpected dose-dependent reductions in platelet count were observed. While platelet count reductions were not observed in rat and dog toxicology studies, subsequent studies in cynomolgus monkeys recapitulated these platelet count reductions with a similar concentration response to that in humans. These studies, along with ex vivo human megakaryocyte maturation studies, demonstrate that platelet lowering is a consequence of DNL inhibition likely to result in impaired megakaryocyte demarcation membrane formation. These observations demonstrate that while DNL is a minor quantitative contributor to global lipid balance in humans, DNL is essential to specific lipid pools of physiological importance.
Subject(s)
Blood Platelets , Lipogenesis/physiology , Acetyl-CoA Carboxylase/antagonists & inhibitors , Acetyl-CoA Carboxylase/metabolism , Animals , Diabetes Mellitus, Type 2/drug therapy , Dogs , Dose-Response Relationship, Drug , Double-Blind Method , Enzyme Inhibitors/pharmacology , Gene Expression/drug effects , Humans , Lipid Metabolism , Macaca fascicularis , Megakaryocytes/physiology , Platelet Count , RatsABSTRACT
Preclinical and clinical data suggest that acetyl-CoA carboxylase (ACC) inhibitors have the potential to rebalance disordered lipid metabolism, leading to improvements in nonalcoholic steatohepatitis (NASH). Consistent with these observations, first-in-human clinical trials with our ACC inhibitor PF-05175157 led to robust reduction of de novo lipogenesis (DNL), albeit with concomitant reductions in platelet count, which were attributed to the inhibition of fatty acid synthesis within bone marrow. Herein, we describe the design, synthesis, and evaluation of carboxylic acid-based ACC inhibitors with organic anion transporting polypeptide (OATP) substrate properties, which facilitated selective distribution of the compounds at the therapeutic site of action (liver) relative to the periphery. These efforts led to the discovery of clinical candidate PF-05221304 (12), which selectively inhibits liver DNL in animals, while demonstrating considerable safety margins against platelet reduction in a nonhuman primate model.
Subject(s)
Acetyl-CoA Carboxylase/antagonists & inhibitors , Drug Delivery Systems , Enzyme Inhibitors/pharmacology , Liver/drug effects , Acetyl-CoA Carboxylase/metabolism , Animals , Enzyme Inhibitors/therapeutic use , Humans , Lipogenesis , Non-alcoholic Fatty Liver Disease/drug therapy , Substrate SpecificityABSTRACT
Dysregulation of hepatic lipid and cholesterol metabolism is a significant contributor to cardiometabolic health, resulting in excessive liver lipid accumulation and ultimately non-alcoholic steatohepatitis (NASH). Therapeutic activators of the AMP-Activated Protein Kinase (AMPK) have been proposed as a treatment for metabolic diseases; we show that the AMPK ß1-biased activator PF-06409577 is capable of lowering hepatic and systemic lipid and cholesterol levels in both rodent and monkey preclinical models. PF-06409577 is able to inhibit de novo lipid and cholesterol synthesis pathways, and causes a reduction in hepatic lipids and mRNA expression of markers of hepatic fibrosis. These effects require AMPK activity in the hepatocytes. Treatment of hyperlipidemic rats or cynomolgus monkeys with PF-06409577 for 6weeks resulted in a reduction in circulating cholesterol. Together these data suggest that activation of AMPK ß1 complexes with PF-06409577 is capable of impacting multiple facets of liver disease and represents a promising strategy for the treatment of NAFLD and NASH in humans.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Enzyme Activators/pharmacology , Hepatocytes/enzymology , Indoles/pharmacology , Liver/enzymology , Non-alcoholic Fatty Liver Disease , Animals , Cell Line , Haplorhini , Hepatocytes/pathology , Humans , Liver/pathology , Mice , Mice, Knockout , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/enzymology , Non-alcoholic Fatty Liver Disease/pathology , RatsABSTRACT
The correlation among clinicopathological parameters of myocardial damage was investigated in rats administered a single subcutaneous dose of isoproterenol at 0 (saline), 0.04, 0.4 and 4 mg/kg. Total lactate dehydrogenase (LDH), creatine kinase (CK), and their isoenzymes (LDH-1, LDH-2 and CK-MB), as well as troponin I and tropinin T, were measured 4 h after the administration of the drug. Troponin I was determined by a chemiluminescence method using Bayer Centaur and DPC Immulyze, as well as by ELISA. Troponin T was assayed semi-quantitatively using Trop T Sensitive. A high correlation was found among LDH isoenzymes, troponin I (Centaur) and troponin T. The present result provides a baseline for interpreting changes in the different parameters of myocardial damage assayed by different methods in toxicity studies.
Subject(s)
Creatine Kinase/blood , Heart/drug effects , Isoproterenol/toxicity , L-Lactate Dehydrogenase/blood , Myocardium/pathology , Toxicity Tests/methods , Troponin I/blood , Troponin T/blood , Animals , Biomarkers/blood , Injections, Subcutaneous , Isoenzymes/blood , Isoproterenol/administration & dosage , Male , Rats , Rats, Inbred StrainsABSTRACT
The hepatocarcinogenic potential of 9-(4'-aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorharman, APNH) was investigated using male and female p53 deficient mice. Incidence of oval cell hyperplasia was 2/14 (14.3%), 14/23 (60.9%), and 2/10 (20%) in p53 nullizygous (-/-), heterozygous (+/-), and wild type (+/+) mice, respectively, exposed to 30 ppm APNH for 15 weeks, while hepatocellular anisonucleosis was observed only in APNH-treated p53 (-/-) mice. At 40 weeks, hepatocellular carcinomas had developed in 16/46 (34.8%) and 10/27 (37.0%) of female p53 (+/-) and (+/+) mice in contrast to only 1/45 (2.2%) and 2/12 (16.7%) in their male counterparts, respectively, without any detectable p53 gene mutations. Dose-dependent APNH-DNA adduct formation and transcriptional induction of CYP 1A1, but not CYP 1A2, was revealed with 7-day APNH treatment using female C57BL/6J mice. These results suggested hepatocarcinogenicity of APNH in mice could be linked to the liver microenvironment including hormonal milieu but independent of p53 expression and p53 gene mutations.
Subject(s)
Indoles/toxicity , Liver Neoplasms, Experimental/chemically induced , Pyridines/toxicity , Tumor Suppressor Protein p53/deficiency , Animals , Cytochrome P-450 CYP1A1/drug effects , DNA Adducts/drug effects , Dose-Response Relationship, Drug , Female , Liver Neoplasms, Experimental/genetics , Liver Neoplasms, Experimental/pathology , Male , Mice , Polymerase Chain Reaction , Polymorphism, Single-Stranded Conformational , Tumor Suppressor Protein p53/geneticsABSTRACT
Polycystic kidney disease (PKD) is a cystic genetic disorder of the kidneys which is typically associated with cystic bile duct dilatation in the liver in humans, and domestic and laboratory animals. In humans, there are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD). ADPKD is caused by mutations in PKD1 or PKD2 gene while ARPKD is caused by mutation or loss of the PKHD1 (polycystic kidney and hepatic disease 1) gene. Here we report a morphologically confirmed case of spontaneous PKD in a Sprague-Dawley rat in which anatomic pathology examination revealed numerous cystic changes in the kidney and liver. Lesions consisted of marked cystic dilatations of renal tubules, and moderate cystic dilatations of intrahepatic bile ducts with portal fibrosis. We present detailed histologic features of the spontaneous PKD and compare them with disease model rats carrying an autosomal recessive PKHD 1 gene mutation.
Subject(s)
Polycystic Kidney Diseases/veterinary , Rats, Sprague-Dawley/genetics , Animals , Kidney/pathology , Kidney Tubules, Collecting/pathology , Liver/pathology , Male , Polycystic Kidney Diseases/genetics , Polycystic Kidney Diseases/pathology , Rats , Receptors, Cell Surface/genetics , Rodent DiseasesABSTRACT
Summation of initiation activities of different carcinogens in the liver after partial hepatectomy (PH) was investigated with reference to induction of glutathione S-transferase placental form (GST-P) positive foci. Firstly, effects of repeated administration of 1,2-dimethylhydradine (DMH) were compared with the results of a single administration of the same total dose (Expt. I). Subsequently, we studied summation of initiation potential with serial administration of DMH with diethylnitrosamine (DEN) or N-bis (2-hydroxpropyl)-nitrosamine (DHPN). In Expt. I, induction of GST-P-positive foci by multiple low-dose administration was equal to that with the single large-dose treatment. In order to avoid toxicity in hepatectomized rats, the low repeated-dose approach appeared superior. In Expt. II, the numbers of GST-P-positive foci in the groups treated with DMH plus DHPN or DMH plus DEN were significantly higher than those in the groups receiving the carcinogens singly. It is concluded that there is summation of initiation potential with doses of a single or multiple carcinogens. These results suggest that the present initiation assay model is useful to investigate summation of initiation activities of various environmental chemicals.