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.     

Development of a Mechanism-Based Dosimetry Model for 2,4,4-Trimethyl-2-pentanol-lnduced {alpha}2u-Globulin Nephropathy in Male Fischer 344 Rats

A mechanism-based dosimetry model was developed to describe2,4,4-trimethyl-2-pentanol (TMP-2-OH) dosimetry and renal 2u-globulin(2u) nephropathy in the male Fischer 344 rat. Experimental datawere collected to estimate the chemical-specific parameters(metabolic constants, tissue solubility, and oral absorptionrate) necessary to describe TMP-2-OH dosimetry in male rats.The concentrations of 2u and TMP-2-OH were measured in malerats up to 64 hr after a single oral dose of TMP-2-OH (6, 60,or 600 mg/kg). The model predicted the time course behaviorof TMP-2-OH and 2u in the kidney, but overestimated their renalconcentrations by two or threefold. Simulations of renal 2uconcentration were sensitive to changes in TMP-2-OH-2u-bindingaffinity and degradation rate of the TMP-2-OH-protein complex.In contrast, simulation of the concentration of TMP-2-OH inthe kidney was most sensitive to the amount of protein present.Oral absorption of TMP-2-OH was dose dependent. The model predictedthat 2u and TMP-2-OH concentration in the kidney is sensitiveto changes in the rate of TMP-2-OH absorbed after oral administration.This model permitted a more rigorous evaluation than has previouslybeen possible of the combination of protein characteristicsand chemical dosimetry required for the accumulation of 2u inthe kidney of male rats. The behavior of the model is consistentwith the qualitative aspects of the 2u hypothesis. However,further characterization of 2u distribution and renal hydrolysiswill be required in order to fully characterize the hypothesisat the quantitative level.     

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.     

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.     

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.     

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.     

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.     

Phytoestrogens and Their Human Metabolites Show Distinct Agonistic and Antagonistic Properties on Estrogen Receptor {alpha} (ER{alpha})and ER{beta} in Human Cells

Figure 3 and Table 3 for this article should have run as presentedbelow. The Publisher regrets the error. View larger version (35K): [in this window] [in a new window]   FIG. 3. Transactivational potencies and     

Metabolism of {alpha}-Olefin Sulfonate (AOS) in Rats

Metabolism of -Olefin Sulfonate (AOS) in Rats. Inoue, S., O'Grodnick,J.S. and Tomizawa, S. (1982). Fundam. Appl. Toxicol. 2:130-138.The metabolic fate of ¹⁴C-AOS (a mixture of ¹⁴C-sodium alkenyl(2)sulfonate and ¹⁴C-sodium 3-hydroxy alkane sulfonate) has beenstudied in rats by a single oral and intravenous injection of100 mg (50 µCi)/kg and 10 mg (5 µCi)/kg, respectively.After oral administration, ¹⁴C-AOS was rapidly absorbed fromthe gastrointestinal tract. The blood level of ¹⁴C-activityreached its peak 3 hr after dosing and then declined. Twenty-fourhr after the dose, about 0.8%/g of the ¹⁴C-AOS given was detectedin cecum content, but in other tissues the figures were under0.02% dose/g. Within 24 hr after the dose, 72% of the dose wasexcreted in the urine and 22% in the feces, while the excretionin the bile was 4.3% within 12 hr. The administered radioactivitywas rapidly eliminated from the whole body within 24 hr. Afterintravenous injection, half of the administered dose of radioactivitywas excreted within 1 hr. In the 0–6 hr interval post-dose,90% of the dose was excreted in the urine. No intact ¹⁴C-AOSwas detected in any of the urine samples after oral and intravenousdoses. The metabolite was apparently more polar than intact¹⁴C-AOS, and results from data of electrophoresis and equilibriumdialysis indicated that intact ¹⁴C-AOS can bind with proteins,while the metabolites cannot. The metabolite was found to containalcoholic, unsaturated and sulfonic acid functionalities. Itis suggested that the metabolite may be a hydroxylated or polyhydroxylatedsulfonic acid of shorter chain length than AOS. These resultssuggest that ¹⁴C-AOS is rapidly absorbed, metabolized and excreted,therefore, no accumulation of ¹⁴C-AOS occurs.     

Leydig Cell Hyperplasia and Adenomas in Mice Treated with Finasteride, a 5{alpha}-Reductase Inhibitor: A Possible Mechanism

Finasteride is a selective inhibitor of the enzyme 5-reductasewhich is responsible for the conversion of testosterone (T)to dihydrotestosterone (DHT). Finasteride is indicated for thetreatment of benign prostatic hyperplasia in man ({small tilde}0.1mg/kg/day). The effect of long-term treatment was studied inmice given high doses (2.5, 25, and 250 mg/kg/day) of finasteridefor 83 weeks. In finasteride-treated mice, increased incidencesof testicular Leydig cell hyperplasia (52% compared to 24% incontrol group) at doses equal to or greater than 25 mg/kg/dayand Leydig cell adenomas (32% compared to 0.5% in control group)at 250 mg/kg/day were observed. There were no drug-related effectson the seminiferous tubules. Since luteinizing hor mone (LH)is a trophic hormone for Leydig cells, short-term studies (5to 14 weeks) were done to investigate the relationship betweenLeydig cell hyperplasia and serum LH levels in finasteride-treatedmice. In these studies, there was a positive correlation betweenthe drug-related increased incidence of Leydig cell hyperplasiaand a statistically significant (p 0.05) increase in serum LHlevels in finasteride-treated (250 mg/kg/day) mice. Furthermore,studies in castrated male mice showed that the suppression ofserum LH levels by T is reversible by inhibition of conversionof T to DHT with finasteride (250 mg/kg/day), supporting thehypothesis that DHT is involved in the regulation of LH releasein mice. The data presented support the conclusion that theeffects of finasteride on Leydig cells appear to be secondaryto increased serum LH levels and that they occur only at veryhigh doses when compared to the therapeutic dose (approximately0.1 mg/kg/day) in man.     

Effects of Lifelong Administration of {beta}-Phenylisopropylhydrazine Hydrochloride and Thiocarbamylhydrazine in Mice

Effects of Lifelong Administration of ß-Phenylisopropyl-hydrazinehydrochloride and thiocarbamylhydrazine in mice. Toth, B. (1982).Fundam. Appl. Toxicol. 2:173-176. ß-Phenylisopropylhydrazinehydrochloride and thiocarbamylhydrazine were separately administeredas 0.0312 and 0.0156% solutions in drinking water for life torandomly bred Swiss mice. The consumption of the chemicals resultedin no detectable tumorigenic effects in the treated animals,and it is therefore concluded that these compounds are apparentlynoncarcinogenic under the present experimental conditions.     

Toxicokinetics of Nickel in Mice Studied with the {gamma}-Emitting Isotope 57Ni

The -emitting isotope ⁵⁷Ni was generated in a cyclotron to allowwhole-body counting of laboratory animals dosed with nickel.⁵⁷NiCl₂ was administered either orally by gastric intubationor by intraperitoneal injection to groups of mice in doses equivalentto the average human daily dietary nickel intake per mass unit.When given orally, the whole-body retention (WBR) was 0.02–0.36%of the administered dose at 45–75 hr. When given intraperitoneally,the WBR was 1–6% at 20–50 hr. After adjustment forthe rapid excretion of systemic nickel, the intestinal absorptioncould be estimated to be 1.7–10%. The relative WBR didnot vary with the magnitude of the dose within 0.05–5µmol Ni/kg given orally or 0.005–0.5 µmol/kggiven intraperitoneally. At 8 hr, the tissue concentration washighest in the kidneys, followed by the carcass, lungs, testicles,liver, and the spleen. After 20 hr, the highest concentrationswere still found in the kidneys followed by the lungs, the liver,and the carcass. At 20 hr after oral administration, 50–70%of ⁵⁷Ni retained in the body was within the carcass. The secondhighest nickel content was found in the kidneys, followed bythe liver and lungs. Whereas nickel in the kidneys was rapidlyexcreted, the elimination from the lungs and liver was relativelyslow, thereby, after 40 hr, resulting in a higher nickel contentin the liver than that in the kidneys. When nickel was givenintraperitoneally, practically no nickel was transported viathe portal vein to the liver after 20 hr, resulting in a lownickel content in the liver and a higher content in the kidney.These results document that the use of ⁵⁷Ni for studies on nickeltoxicokinetics is feasible and useful, and that the method isespecially well suited for comparative studies with a durationof up to 6 days.     

Effects of Recombinant Murine Interferon-{gamma} on Pregnant Mice and Their Fetuses

Effects of Recombinant Murine Interferon- on Pregnant Mice andTheir Fetuses. KATO, I., KIMURA, S., FURUHASHI, T., NAKAYOSHI,H., TAKAYAMA, S., AND UENISHI, N. (1990). Fundam. Appl. Toxicol.14, 658–665. Recombinant murine interferon- (Rec-MuIFN-)was administered intramuscularly to C3H/HeNCrj mice on Days6-15 of gestation at dosage levels of 8 x 10⁵, 4 x 10⁶, and2 x 10⁷ u/kg/day. Dams were killed for examination of fetuseson Day 18 of gestation. Pregnant females that received 2 x 10⁷u/kg/day of Rec-MuIFN- showed uterine bleeding on Days 10–15of gestation and could not maintain their pregnancy. These damsdied on Days 13–17orwerekilled/ieWrem/sonDays 10–15for examination, and therefore no fetal data were availablefor this group. In the 2 x 10⁷ u/kg/day group, the mean absoluteweights of the lung and spleen increased and the mean absoluteweight of the liver, red blood cells (RBC), hematocrit, andhemoglobin decreased significantly. Surviving dams in the 8x 10³ and 4 x 10⁶ u/kg/day groups showed significant increasesin the mean absolute weights of the lung, liver, kidneys, andspleen and a decrease in platelet count. Significant increasesin the weights of the heart and ovaries and decreases in RBC,hematocrit, and hemoglobin were observed in the 4 x 10⁶ u/kg/daygroup. Histopathological examination revealed increased extramedullaryhema-topoiesis in the spleen of the 4 x 10⁶ and 2 x 10⁷ u/kg/daygroups. Fetuses showed no external, visceral, or skeletal malformationsand variations caused by the administration of Rec-MuIFN-7 inany of the treated groups. Although a slight but statisticallysignificant decrease in fetal body weight and a delay in ossificationwere seen in fetuses in the 4 x 10⁷ u/kg/day group, these findingswere considered to be the result of maternal toxicity and notfetal toxicity. No fetal effects were observed i n the 8 x 10⁵u/kg/day group.     

Possible Involvement of Prostaglandins in Increases in Rat Plasma Adrenocorticotropic Hormone and Corticosterone Levels Induced by Radiation and Interleukin-1{alpha} Alone or Combined

Exposing rats to 1–10 Gy of ionizing radiation increasedplasma adrenocorticotropic hormone (ACTH) and corticoste-rone(CORT) levels. In both irradiated and nonirradiated rats, recombinanthuman interleukin-1 (rhIL-1 1 hr before radiation/sham exposure)enhanced plasma ACTH and CORT levels. Indomethacin, a cyclooxygenaseinhibitor, attenuated plasma ACTH and CORT levels induced byradiation. Indomethacin also attenuated ACTH and CORT levelsinduced by radiation and interleukin-1 alone or combined. Theseresults suggest that prostaglandins are involved in the increasein plasma ACTH and CORT levels induced by radiation and rhIL-1alone or combined.     

Pharmacological dose of {alpha}-tocopherol induces cardiotoxicity in Wistar rats determined by echocardiography and histology

The effect of pharmacological dose of α-tocopherol on heart health was determined in Wistar rats. Animals were randomly assigned to either C (control, n = 11) or E (α-tocopherol, n = 11) group. Animals received corn oil (C) or α-tocopherol dissolved in corn oil (250 mg α-tocopherol/[kg body wt/day]) (E) by gavage for a 7-week period. Rats underwent echocardiogram and were analyzed for cardiomyocyte histology and cardiac α-tocopherol absorption at the end of the study period. As compared to the C group, α-tocopherol-supplemented group showed significantly (p < 0.05) lower body weight (E, 412.8 g vs C, 480.3 g) and total cardiac weight (E, 0.94 g vs C, 1.08 g); cardiomyocyte histological impairment; smaller left ventricle (LV) (LV end-diastolic diameter (E, 7.22 mm vs C, 7.37 mm), lower LV systolic [left ventricle fractional shortening (E, 47.6% vs C, 53.6%) and ejection fraction ratio (E, 85.4 vs C, 89.9)] and diastolic [early peak velocities of diastolic transmitral flow (E, 64.6 cm/sec vs C, 75.1 cm/sec)] function. The α-tocopherol uptake in target tissue was confirmed by determination of α-tocopherol concentration medians in cardiac tissue (E, 109.91 nmol/kg vs C, 52.09 nmol/kg). The current study indicates that pharmacological dose of α-tocopherol supplementation can induce cardiotoxicity in healthy rats.     

The Effects of {alpha},{beta}-Unsaturated Aldehydes on Hepatic Thiols and Thiol-Containing Enzymes

The effects of series of ,ß-unsaturated aldehydeson hepatic giutathione, cytochrome P450, and NADPH-cytochromec reductase activity were compared with time. Male F-344 ratswere dosed with muconaldehyde (36 µmol/kg), acrolein (89µmol/ kg), crotonaldehyde (450 µmol/kg), or thesaturated aldehyde propionaldehyde (89 µmol/kg) and terminated0.5, 4, or 24 hr later. Acroiein or muconaldehyde reduced glutathioneto 51 and 75% of controls, respectively, at 4 hr; glutathionereturned control values at 24 hr. Only at 24 hr, acrolein, muconaldehyde,or crotonaldehyde decreased cytochrome P450 to 61, 71, and 67%of control values, respectively; ethylmorphine N-demethylationwas decreased to a greater extent, i.e., to 35, 60, and 23%of controls. The reductase activity was unchanged at any timefollowing the treatment with reactive aldehydes which were nothepatotoxic (as shown by glucose 6-phosphatase activity, histologicalchanges, or serum enzymes). Propionaidehyde changed none ofthese activities. Acroiein (44.5 mol/kg) given 4 hr prior tophenobarbital (50 mg/kg) for two consecutive days decreasedthe phenobarbital induction of cytochrome P450 45% of phenobarbitalalone. This treatment also decreased the 2, 2ß, 6ß,l6, and 16ß hydroxylation of testosterone as wellas androstenedione formation showing effects on individual cytochromeP450 isozymes. NADPH-cytochrome c reductase induction was notdecreased by this treatment, thus indicating that in vivo thesechanges are due to a mechanism other than generalized inhibitionof protein synthesis.     

Hepatoprotective Effects of the Shark Bile Salt 5{beta}-Scymnol on Acetaminophen-Induced Liver Damage in Mice

The hepatoprotective effect of the shark bile salt 5ß-Scymnolhas been studied in the model of acute hepatotoxicity inducedby administration of acetaminophen (APAP, paracetamol). 5ß-Scymnolat doses of 20, 35, and 70 mg/kg intraperitoneally (ip) decreasedsignificantly the serum activity of alanine aminotransferase,sorbitol dehydrogenase, and lactate dehydrogenase (p < 0.05)caused by APAP treatment (350 mg/kg ip) alone. The highest doseof 5ß-Scymnol remained hepatoprotective when administered4 hr after the APAP overdose. N-Acetylcysteine (NAC) is protectiveagainst APAP-induced hepatotoxicity at 250 and 500 mg/kg (ip)when administered up to 3 hr after APAP overdose, as shown bya significant reduction in serum enzyme activity. Coadministrationof 5ß-Scymnol (70 mg/kg) and NAC (250 mg/kg) alsoreduced serum enzyme levels and histopathological effects; however,a similar level of hepatoprotection was conferred by 5ß-Scymnoltreatment alone. In addition, 5ß-scymnol has potenthydroxyl radical quenching activity as it markedly inhibiteddeoxyribose degradation in a ferrous/ascorbate Fenton reactionsystem. These results indicate a possible role for the use of5ß-scymnol, either alone or concomitant with NAC,in the prevention of hepatic necrosis following toxic dosesof APAP.     

alpha 2u-Globulin nephropathy, renal cell proliferation, and dosimetry of inhaled tert-butyl alcohol in male and female F-344 rats.

tert-Butyl alcohol (TBA) has been shown to cause kidney tumors in male rats following chronic administration in drinking water. The objective of the present study was to determine whether TBA induces alpha 2u-globulin (alpha 2u) nephropathy (alpha 2u-N) and enhanced renal cell proliferation in male, but not female, F-344 rats, and whether the dosimetry of TBA to the kidney is gender specific. Male and female F-344 rats were exposed to 0, 250, 450, or 1750 ppm TBA vapors 6 h/day for 10 consecutive days to assess alpha 2u-nephropathy and renal cell proliferation and for 1 and 8 days to evaluate the dosimetry of TBA following a single and repeated exposure scenario. Protein droplet accumulation was observed in kidneys of male rats exposed to 1750 ppm TBA, with alpha 2u-globulin immunoreactivity present in these protein droplets. A statistically significant increase in alpha 2u concentration in the kidney, as measured by an enzyme-linked immunosorbent assay, was observed in male rats exposed to 1750 ppm TBA with a exposure-related increase in renal cell proliferation. Renal alpha 2u concentration was positively correlated with cell proliferation in male rat kidney. No histological lesions or increased renal cell proliferation was observed in female rats exposed to TBA compared to controls. The TBA kidney:blood ratio was higher at all concentrations and time points in male rats compared with female rats, which suggests that TBA is retained longer in male rat kidney compared with female rat kidney. Together these data suggest that TBA causes alpha 2u-N in male rats, which is responsible for the male rat-specific increase in renal cell proliferation.     

Toxicity and Carcinogenicity of {Delta}9-Tetrahydrocannabinol in Fischer Rats and B6C3F1 Mice

⁹-Tetrahydrocannabinol (⁹-THC) was studied for potential carcinogenicityin rodents because it is the principal psychoactive ingredientin marihuana and it has potential medicinal uses. ⁹-THC in cornoil was administered by gavage to groups of male and femaleFischer rats and B6C3F1 mice at 0, 5, 15, 50, 150, or 500 mg/kg,5 days a week for 13 weeks and for 13-week plus a 9-week recoveryperiod, and to groups of rats at 0, 12.5, 25, or 50 mg/kg andmice at 0, 125, 250, or 500 mg/kg, 5 times a week for 2 years.In all studies, mean body weights of dosed male and female ratsand mice were lower than controls but feed consumptions weresimilar. Convulsions and hyperactivity were observed in dosedrats and mice; the onset and frequency were dose related. SerumFSH and LH levels hi all dosed male rats and corticosteronelevels in 25 mg/kg female rats were significantly higher thancontrols at 15 months in the 2-year studies. ⁹-THC administrationfor 13 weeks induced testicular atrophy and uterine and ovarianhypoplasia; the lesions persisted in a 9-week recovery period.In the 2-year studies, survival of dosed rats was higher thancontrols; that of mice was similar to controls. Incidences oftesticular interstitial cell, pancreas and pituitary gland adenomasin male rats, mammary gland fibroadenoma and uterus stromalpolyp in female rats, and hepatocellular adenoma/carcinoma inmale and female mice were reduced in a dose-related manner.Decreased tumor incidences may be at least in part due to reducedbody weights of dosed animals. Incidences of thyroid gland follicularcell hyperplasia were increased in all dosed groups of maleand female mice, and follicular cell adenomas were significantlyincreased in the 125 mg/kg group of males, but there was noevidence of a dose-related trend in proliferative lesions ofthe thyroid. There was no evidence that ⁹-THC was carcinogenicin rats or mice.