The arrest of hemorrhage in mechanical injuries to parenchymatous organs

The work describes results of the application of a new highly effective hemostatic drug--Caprofer. The investigations were performed in 61 rabbits who were given graded injuries of the liver, kidney and spleen. In all the cases hemostasis made its appearance quickly within 1-20 sec. after the application of Caprofer. Reliability of hemostasis was checked by the method of hydropressure of the organs under study which was shown to be very high. Caprofer was used under clinical conditions in 61 patients in operations for traumas and diseases of the liver, kidney, spleen, gallbladder and in resection of the prostate. The results obtained speak of high efficiency of Caprofer for parenchymatous bleedings. Pronounced adhesive properties of the drug were noted as well as the absence of undesirable side effects.     

Calreticulin: an intracellular Ca++-binding protein abundantly expressed and regulated by androgen in prostatic epithelial cells

Calreticulin was identified in a screen for androgen-response genes in the rat ventral prostate. Northern blot and Western blot analyses in the rat model showed that both calreticulin messenger RNA and protein are down-regulated by castration and up-regulated by androgen replacement in the prostate. Northern blot analysis showed that calreticulin expression level in the prostate is much higher than that in seminal vesicles, heart, brain, muscle, kidney, and liver. The regulation of calreticulin expression by androgen is only observed in the prostate and seminal vesicles, two male secondary sex organs. The induction of calreticulin by androgen in prostate organ culture partially resists protein synthesis inhibition, suggesting that calreticulin is a direct androgen-response gene. In situ hybridization and immunohistochemistry studies showed that calreticulin is an intracellular protein in prostatic epithelial cells. Because calreticulin is a major intracellular Ca++-binding protein with 1 high-affinity and 25 low-affinity Ca binding sites, our observations suggest that calreticulin is a promising candidate that mediates androgen regulation of intracellular Ca++ levels and/or signals in prostatic epithelial cells. The expression of calreticulin is also regulated by androgen in the mouse and human prostate, suggesting that androgen regulation and function of calreticulin in the prostate are conserved evolutionarily.     

Stability, tissue metabolism, tissue distribution and blood partition of azosemide

Stability of azosemide after incubation in various pH solutions, human plasma, human gastric juice, and rat liver homogenates, metabolism of azosemide after incubation in 9000 g supernatant fraction of various rat tissue homogenates in the presence of NADPH, tissue distribution of azosemide and M1 after intravenous (i.v.) administration of azosemide, 20 mg kg-1, to rats, and blood partition of azosemide between plasma and blood cells from rabbit blood were studied. Azosemide seemed to be stable for up to 48 h incubation in various pH solutions ranging from two to 13 at an azosemide concentration of 10 micrograms mL-1; more than 93.4% of azosemide was recovered, and a metabolite of azosemide, M1, was not detected. However, the drug was unstable in pH1 solution: 75.8% of azosemide was recovered and 2.16 micrograms mL-1 of M1 (expressed in terms of azosemide) was formed after 48 h incubation in pH 1 solution at an azosemide concentration of 10 micrograms mL-1. Azosemide was stable in both human plasma and rat liver homogenates for up to 24 h incubation at an azosemide concentration of 1 microgram mL-1, and in human gastric juice for up to 4 h incubation at an azosemide concentration of 10 micrograms mL-1. However, all rat tissues studied had metabolic activity for azosemide in the presence of NADPH, with heart having a considerable metabolic activity: approximately 22% of azosemide disappeared and 9.32 micrograms of M1 was formed per gram of heart (expressed in terms of azosemide) after 30 min incubation of 50 micrograms of azosemide in 9000 g supernatant fraction of heart homogenates. The tissue to plasma ratios of azosemide (T/P) were greater than unity only in the liver (1.26) and kidney (1.74); however, M1 showed high affinity for all tissues studied except the brain and spleen when each tissue was collected at 30 min after i.v. administration of azosemide to rats. The equilibrium plasma to blood cell concentration ratios of azosemide were independent of azosemide blood concentrations: the values were 2.78-4.25 at azosemide blood concentrations of 1, 10, and 20 micrograms mL-1 in three rabbits. There was negligible 'blood storage effect' of azosemide, especially at low blood concentrations of azosemide, such as 1 and 10 micrograms mL-1.     

Species differences in the glutathione transferase GSTT1-1 activity towards the model substrates methyl chloride and dichloromethane in liver and kidney

Glutathione transferase (GST) GSTT1-1 is involved in the biotransformation of several chemicals widely used in industry, such as butadiene and dichloro methane DCM. The polymorphic hGSTT1-1 may well play a role in the development of kidney tumours after high and long-term occupational exposure against trichloroethylene. Although several studies have investigated the association of this polymorphism with malignant diseases little is known about its enzyme activity in potential extrahepatic target tissues. The known theta-specific substrates methyl chloride (MC) dichloromethane and 1,2-epoxy-3-(p-nitrophenoxy)propane (EPNP) were used to assay GSTT1-1 activity in liver and kidney of rats, mice, hamsters and humans differentiating the three phenotypes (non-conjugators, low conjugators, high conjugators) seen in humans. In addition GSTT1-1 activity towards MC and DCM was determined in human erythrocytes. No GSTT1-1 activity was found in any tissue of non-conjugators (NC). In all organs high conjugators (HC) showed twofold higher activity towards MC and DCM than low conjugators (LC). The activity in human samples towards EPNP was too close to the detection limit to differentiate between the three conjugator phenotypes. GSTT1-1 activity towards MC was two to seven-times higher in liver cytosol than in kidney cytosol. The relation for MC between species was identical in both organs: mouse > HC > rat > LC > hamster > NC. In rats, mice and hamsters GSTT1-1 activity in liver cytosol towards DCM was also two to seven-times higher than in the kidney cytosol. In humans this activity was twice as high in kidney cytosol than in liver cytosol. The relation between species was mouse > rat > HC > LC > hamster > NC for liver, but mouse > HC > LC/rat > hamster/NC for kidney cytosol. The importance to heed the specific environment at potential target sites in risk assessment is emphasized by these results.     

Expression and characterization of recombinant type 2 3 alpha-hydroxysteroid dehydrogenase (HSD) from human prostate: demonstration of bifunctional 3 alpha/17 beta-HSD activity and cellular distribution

In androgen target tissues, 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) may regulate occupancy of the androgen receptor (AR) by catalyzing the interconversion of 5alpha-dihydrotestosterone (5alpha-DHT) (a potent androgen) and 3alpha-androstanediol (a weak androgen). In this study, a 3alpha-HSD cDNA (1170 bp) was isolated from a human prostate cDNA library. The human prostatic 3alpha-HSD cDNA encodes a 323-amino acid protein with 69.9%, 84.1%, 99.4%, and 87.9% sequence identity to rat liver 3alpha-HSD and human type 1, type 2, and type 3 3alpha-HSDs, respectively, and is a member of the aldo-keto reductase superfamily. The close homology with human type 2 3alpha-HSD suggests that it is either identical to this enzyme or a structural allele. Surprisingly, when the recombinant protein was expressed and purified from Escherichia coli, the enzyme did not oxidize androsterone when measured spectrophotometrically, an activity previously assigned to recombinant type 2 3alpha-HSD using this assay. Complete kinetic characterization of the purified protein using spectrophotometric, fluorometric, and radiometric assays showed that the catalytic efficiency favored 3alpha-androstanediol oxidation over 5alpha-DHT reduction. Using [14C]-5alpha-DHT as substrate, TLC analysis confirmed that the reaction product was [14C]-3alpha-androstanediol. However, in the reverse reaction, [3H]-3alpha-androstanediol was oxidized first to [3H]-androsterone and then to [3H]-androstanedione, revealing that the expressed protein possessed both 3alpha- and 17beta-HSD activities. The 17beta-HSD activity accounted for the higher catalytic efficiency observed with 3alpha-androstanediol. These findings indicate that, in the prostate, type 2 3alpha-HSD does not interconvert 5alpha-DHT and 3alpha-androstanediol but inactivates 5alpha-DHT through its 3-ketosteroid reductase activity. Levels of 3alpha-HSD mRNA were measured in primary cultures of human prostatic cells and were higher in epithelial cells than stromal cells. In addition, elevated levels of 3alpha-HSD mRNA were observed in epithelial cells derived from benign prostatic hyperplasia and prostate carcinoma tissues. Expression of 3alpha-HSD was not prostate specific, since high levels of mRNA were also found in liver, small intestine, colon, lung, and kidney. This study is the first complete characterization of recombinant type 2 3alpha-HSD demonstrating dual activity and cellular distribution in the human prostate.     

8-hydroxyguanine levels in nuclear DNA and its repair activity in rat organs associated with age

8-Hydroxyguanine (8-OH-Gua) is one of the most abundant types of oxidative DNA damage. The levels of 8-OH-Gua, and its repair activity, were quantified in 3-week-, 5-month-, and 30-month-old male Sprague-Dawley rat organs such as liver, kidney, spleen, lung, small intestine, and brain. The levels of 8-OH-Gua were significantly higher in the 5-month-old rat kidney and brain and 30-month-old rat spleen when compared to that of the 3-week-old rats. However, no significant differences were found in the organs between 5- and 30-month-old rats that were due to the aging process. The repair activity levels of kidney, spleen, and lung were higher than those of liver, small intestine, and brain. This pattern was consistent for the three age stages.     

Analytical findings in a fatal poisoning with silver compound

A 69-year-old male radio technician drank an unknown amount of a liquid and died within 5 h at a hospital. Mainly silver, potassium, and calcium, among other substances, were found in the residue of the liquid from the empty bottle by means of the spectrographic method (30.7% silver and 25.5% potassium using atomic absorption spectometry [AAS] method). The toxicological analysis of the postmortem material for silver performed by the flame AAS method (stomach, 2.43 micrograms/g; intestines, 1.12 micrograms/g; liver, 6.29 micrograms/g; kidney, 4.85 micrograms/g; spleen, 30.1 micrograms/g; heart, 10.8 micrograms/g; lung, 14.8 micrograms/g; and brain, 0.61 microgram/g) confirmed fatal silver compound poisoning. The results were verified by the standard additions technique and recovery examination. However, no increase in the potassium concentrations was observed in the postmortem material. There have been no data in available literature on the distribution of silver in tissues in people after oral administration of silver salts.     

Mapping the in vivo distribution of herpes simplex virions

We describe a method for labeling enveloped viral particles with a radiotracer, indium-111, allowing labeled viruses to be traced in vivo by nuclear imaging. After initial optimization experiments, a labeling efficiency of 83% (incorporation yield) was achieved for herpes simplex virus (HSV), resulting in a specific activity of 30 microCi/10(9) PFU. The labeling procedure did not significantly reduce the infectivity of the labeled virus and the virus did not release any significant amounts of the radionuclide within 12 hr after labeling. Sequential imaging of animals after intravenous administration of the labeled virus showed fast accumulation in the liver and redistribution from the blood pool (immediately after injection) to liver and spleen (12-24 hr after injection). At 12 hr after injection 7% of the virus-associated (111)In had been eliminated from the body and the remaining organ distribution of the virus was as follows: spleen 2.87 +/- 0.54% ID/g; liver, 2.60 +/- 0.51% ID/g; kidney, 0.98 +/- 0.31% ID/g; lung, 0.57 +/- 0.10% ID/g; [corrected] and lower amounts in other organs. Our results indicate that the described method allows qualitative and quantitative assessment of viral biodistribution in vivo by nuclear imaging.     

Comparison and significance of respiration and glycolysis of prostatic tissue from various species

The respiration and glycolysis of prostatic tissue from baboons, rhesus monkeys, dogs and rats were compared to the respiration and glycolysis in human prostatic tissue. All the primate prostates had a high glycolytic ability and a low respiration in contrast to the rat and dog prostate. Treatment of baboons with drugs clinically effective against prostatic cancer did not change the prostatic metabolism despite a marked prostatic atrophy. In vitro the drugs reduced respiration markedly. The metabolic similarity between the human and the baboon and rhesus monkey prostate indicates that nonhuman primates should be investigated in the evaluation of chemotherapeutic agents for treatment of prostatic cancer.     

Antiangiogenic effects of the quinoline-3-carboxamide linomide

Linomide (N-phenylmethyl-1,2-dihydro-4-hydroxyl-1-methyl-2-oxoquinoline-3-carboxa mide) has a reproducible in vivo antitumor effect against a series of both androgen responsive and independent Dunning R-3327 rat prostatic cancers. This antitumor effect of linomide is host mediated. One possible mechanism involving the host is that linomide has antiangiogenic activity. An indication that linomide treatment has antiangiogenic activity is the observation that prostatic cancers from linomide treated rats have more focal necrosis than sized matched tumors from untreated rats. To directly test if linomide has antiangiogenic activity, a newly developed Matrigel based quantitative in vivo angiogenic assay was used. These experiments demonstrated that linomide has dose dependent, antiangiogenic activity in vivo in the rat. Additional studies demonstrated that due to its antiangiogenic activity, linomide treatment of rats bearing prostate cancers resulted in a more than 40% decrease in tumor blood flow. Blood flow to a variety of non-tumor bearing organs was not decreased suggesting that linomide selectively inhibits angiogenesis and does not induce loss of established blood vessels. Using as a model the response of human umbilical vein endothelial cells to linomide treatment in a variety of in vitro assays, linomide was demonstrated to have cytostatic but not cytotoxic effect on human umbilical vein endothelial cells at a medium concentration of > or = 100 micrograms/ml. In addition, both endothelial cell chemotactic migration and invasion are steps in angiogenesis inhibited by linomide treatment.     

A new method for evaluation of the antagonistic action of bacterial lactic acid (LAB) on selected pathogenic indicator bacteria

To evaluate whether the in vivo mutagenicity test system using the lacZ transgenic mice (Muta Mouse) may be applied to carcinogenesis studies, both the in vivo mutagenicity and carcinogenicity of benzo[a]pyrene (BP) was tested in mice under the same administration conditions. The eleven organs of the mice on the 14th day after the final oral administration of BP at a dose of 125 mg kg(-1) day(-1) or corn oil for 5 consecutive days were tested for in vivo mutation by the positive-selection method. The data show that the colon had the highest lacZ mutant frequency (37-fold increase over the spontaneous frequency), followed by the ileum > forestomach > bone marrow, spleen > glandular stomach > liver, lung > kidney and heart. No significant mutations were found in the brain. These results may suggest that, in general, the organs with rapidly proliferative tissues have a marked increase in vivo mutant frequencies under the conditions of this experimental design. The forestomach and lymphatic organs including the spleen (malignant lymphoma) were the main target organs for BP carcinogenesis by 5 daily oral doses of 75 and 125 mg kg(-1) day(-1). These results suggest that the mutation results from the transgenic assay with BP reflect the carcinogenicity of BP in the mouse. They also indicate, however, that the magnitude of the in vivo lacZ mutant frequencies induced by BP in different organs did not fully correlate with the target organs for carcinogenicity.     

Immunochemical distribution and immunohistochemical localization of 20beta-hydroxysteroid dehydrogenase in neonatal pig tissues

Immunochemical distribution of 20beta-hydroxysteroid dehydrogenase (HSD) in neonatal pig tissues was investigated by Western blot analysis of the proteins reacting with anti-20beta-HSD antibody. 20beta-HSD was present in all organs investigated: brain, lung, thymus, submandibular gland, heart, liver, kidney, spleen, adrenal gland, testis, epididymis, prostate, vas deferens and seminal vesicle. In particular, high concentrations of 20beta-HSD were detected in the testis, followed by the kidney and liver, by the [125I]-protein A binding method. Immunohistochemical localization of the enzyme was achieved in paraffin sections of the testis, kidney, liver, epididymis, and vas deferens by the streptoavidin-biotin complex method. In the testis, very strong immunostaining was found only in interstitial Leydig cells, whereas the cells in seminiferous tubules, such as Sertoli cells and spermatogenic cells, were entirely negative. In the kidney, strong immunostaining was detected in epithelial cells of Henle's loop. The immunoreactive proteins were also localized in the hepatic lobules of the liver, tall columnar cells of the ductus epididymidis of the epididymis, and mucosal epithelium cells and muscularis of the vas deferens. These observations indicate that tissue distribution of 20beta-HSD is similar to that of carbonyl reductase in the human and rat. However, the specific and abundant expression of 20beta-HSD in testicular Leydig cells of the neonatal pig, which are concerned with the synthesis of androgens, suggests that 20beta-HSD has a very important physiological role in testicular function during the neonatal stage.     

Effects of nonoxynol-9 on vaginal microflora and chlamydial infection in a monkey model

A 58-year-old male with left renal cell carcinoma and prostatic carcinoma occurring synchronously, is reported. He visited our hospital, because of the high level of serum prostate-specific antigen (PSA) pointed out in a health screening by his company. Prostatic cancer was detected in both lobes of the prostate by needle biopsy specimens and histopathology represented moderately > poorly differentiated adenocarcinoma. Magnetic resonance imaging (MRI) and computed tomography (CT) revealed no cancer invasion beyond the prostate and no lymph node metastasis. Bone scintigram showed no abnormal RI accumulation to bone. Therefore, his prostatic cancer was considered to be at stage B2. Abdominal ultrasound echogram showed the mass lesion in the left kidney. CT and angiogram also demonstrated a left renal tumor. Left radical nephrectomy was performed and histopathology showed a mixed subtype of renal cell carcinoma (stage: pT2b, pN0, pM0). Although 94 cases of double cancers associated with genitourinary organs have been reported in the Japanese literature, only 4 cases of double cancers of renal cell carcinoma and prostatic cancer have been reported.     

Cholesterol and oxygenated cholesterol concentrations are markedly elevated in peripheral tissue but not in brain from mice with the Niemann-Pick type C phenotype

Niemann-Pick disease type C (NP-C) is a rare genetic disorder characterized by progressive neurodegeneration, frequent developmental delay and early death. Tissues of affected individuals accumulate large quantities of free cholesterol in lysosomes. Because cytotoxic oxygenated derivatives of cholesterol are known to form readily when cholesterol concentrations are elevated, we searched for these compounds in liver, kidney, spleen and brain from mice with the NP-C phenotype. In order of abundance, we identified 7 alpha- and 7 beta-hydroxycholesterol, 5 alpha, 6 alpha-epoxycholestan-3 beta-ol, 4 beta-hydroxycholesterol, cholest-4-en-3 beta, 7 alpha-diol and cholest-4-en-3 beta, 6 beta-diol in most tissue samples. Cholesterol concentrations in affected mice were increased 3-fold in kidney and 7- to 8-fold in spleen and liver compared to controls (all p < 0.001) but were unchanged in brain. Although oxysterol levels were markedly elevated in nonbrain tissue, the oxysterol and cholesterol concentrations increased proportionally so that oxysterols expressed as percentage of total sterols were the same for all animals (0.34 +/- 0.19% averaged over all organs in affected animals vs 0.40 +/- 0.42% in control mice). In contrast to peripheral tissue, we could not detect any increase in either absolute or relative oxysterol levels in the brains of affected and control mice (49 +/- 61 vs 53 +/- 43 micrograms/g wet weight and 0.45 +/- 0.52 vs 0.47 +/- 0.37%, respectively). Thus, brain sterols are normal in NP-C mice and it is unlikely that an accumulation of cytotoxic oxygenated derivatives of cholesterol could account for the progressive neuropathology seen in the disease.     

Clearance kinetics, biodistribution, and organ saturability of phosphorothioate oligodeoxynucleotides in mice

We examined the dynamics of removal from circulation, tissue distribution, and persistence of phosphorothioate oligodeoxynucleotides (S-ODN) anti-tumor-necrosis-factor and a control of random sequence (randomer) in mice. After intravenous injection, the majority (96%) of S-ODN cleared rapidly from the circulation in the first two phases. In the first phase, 37.8 +/- 2.3% of the radioactivity had a mean half-life (t1/2) of 2.0 +/- 0.4 minutes. In the second phase, 58.1 +/- 1.5% of the radioactivity cleared with t1/2 of 12.6 +/- 0.2 minutes. The catabolic phase, constituting a minor proportion (4.1 +/- 0.8% of the total radioactivity), had a mean t1/2 of 2.7 +/- 0.5 hours. At a low dose (1 microgram) tissue distribution of both S-ODN anti-tumor-necrosis-factor and randomer were similar. The liver and kidneys were the major organs involved in uptake and removal of S-ODN. Autoradiographic studies showed the liver Kupffer cells to be the major site of uptake and renal urinary space for elimination. The clearance rate from the circulation was increased with the dose of S-ODN. In contrast, the fraction of radioactivity localized in the kidneys, liver, and spleen was decreased with increase in dosage. Furthermore, at a high dose (200 micrograms), the tissue distribution of the S-ODN anti-tumor-necrosis-factor differed significantly from the randomer. These findings have general significance in showing that the liver and kidneys are the major organs for removal of S-ODN and these organs are saturable at high doses. In addition, the results have specific importance in defining different parameters, dose and base composition, that affect utilization of antisense oligonucleotides for controlling gene expression in vivo.     

Widespread expression of beta-defensin hBD-1 in human secretory glands and epithelial cells

We compared the expression of human alpha- and beta-defensins by various human tissues. mRNA for alpha-defensins HNP1-3, abundant in bone marrow, was detected in peripheral blood leukocytes, spleen and thymus by RT-PCR, which revealed alpha-defensins HD5 and HD6 only in the small intestine. In contrast, the pancreas and kidney expressed high levels of hBD-1 and lower levels of this beta-defensin were found in many organs by RT-PCR (salivary gland > trachea > prostate and placenta > thymus, testis, small intestine). hBD-1 mRNA was produced constitutively by cultured normal human epithelial cells derived from the trachea, bronchi, small airways and the mammary gland. These largely non-overlapping tissue distributions of human alpha- and beta-defensins suggest that hBD-1 may be positioned to defend epithelial cells and mucosae from infection, whereas expression of HNP1-3 in neutrophils and HD5 and HD6 in Paneth cells allows these alpha-defensins to participate in systemic and small intestinal host defenses, respectively.     

Enterocolitis after the surgical treatment of Hirschsprung''s disease: risk factors and financial impact

OBJECTIVE: To determine whether anterograde ejaculation is preserved after transurethral resection of both the prostate and bladder neck (TURP and TURBN). PATIENTS AND METHODS: Between 1994 and 1997, 45 patients (mean age 53.2 years, range 42-62) with bladder neck obstruction and small obstructive adenomas (< 35 g) underwent TURP/TURBN, preserving part of the supramontanal prostate and prostatic urethra for > 1 cm from the verumontanum. They were assessed before and after 0.5-2 years to determine the type of ejaculation, symptom scores and sexual function, and compared with 10 similar patients who had undergone a conventional TURP. RESULTS: With preservation of > 1 cm of the supramontanal prostate, anterograde ejaculation was maintained in 80% of the patients, whereas only one patient in the control group retained anterograde ejaculation. CONCLUSIONS: The preservation of anterograde ejaculation after TURP (in approximately 20% of cases) and after transurethral incision of the prostate (> 90% cases) reported in the literature probably relates more to the presence of an adequate amount of residual prostatic tissue than to the existence of a hypothetical 'pre-prostatic sphincter'.     

Deletional and mutational analyses of the human CD4 gene promoter: characterization of a minimal tissue-specific promoter

Chloroanilines (CA) are widely used chemical intermediates which induce numerous toxicities including hematotoxicity, splenotoxicity, hepatotoxicity and nephrotoxicity. Although chloroaniline-induced hematotoxicity has been studied in detail, little information is available on the organ-directed toxicity seen following exposure to these agents. The purpose of this study was to examine and compare the excretion and distribution of two nephrotoxicant and hepatotoxicant chloroanilines (2- and 4-chloroaniline) to liver, kidney, spleen, plasma and erythrocytes. Subcellular distribution and covalent binding in kidney and liver were also determined. Male Fischer 344 rats (four per group) were administered [14C]-2-chloroaniline or [14C]-4-chloroaniline (0.5 or 1.0 mmol/kg; approximately 50 microCi/rat) intraperitoneally (i.p.). Urine, feces, blood and tissues were collected at 3 and 24 h. Both 2- and 4-chloroaniline-derived radioactivity were primarily renally excreted with < 1% excretion in the feces by 24 h post-treatment. Both chloroanilines accumulated mainly in liver (percentage of administered dose/total tissue), but kidney generally had similar or higher equivalent concentrations (micromol/g tissue) compared to liver. Subcellular distribution revealed that for both chloroanilines, the cytosolic fraction generally had the highest level of radioactivity independent of time or dose. Covalent binding was detected in both liver and kidney, with the highest concentration (pmol/mg protein) of binding observed in the hepatic microsomal fraction regardless of compound, dose or time studied. In general, 2-chloroaniline derived radioactivity was excreted faster, reached peak tissue concentrations earlier, disappeared from tissues faster and had less covalent binding in target tissue at 24 h than 4-chloroaniline-derived radioactivity. These results suggest that the increased toxic potential of 4-chloroaniline as compared to 2-chloroaniline may be due in part to a more prolonged and persistent accumulation of 4-chloroaniline and/or its metabolites in target tissue.