Biomedical subjects

C D Brown

Publications and source records attributed to C D Brown.

At least 37 records · Page 2Linked to original sources

PubMed2000

Characterization of MPP+ secretion across human intestinal Caco-2 cell monolayers: role of P-glycoprotein and a novel Na(+)-dependent organic cation transport mechanism.

1. In the kidney, a number of transport proteins involved in the secretion of permanently charged organic cations have recently been cloned. To evaluate the possible similarities between intestine and kidney in the handling of organic cations we investigated the transport of 1-methyl-4-phenylpyridinium (MPP+) across monolayers of intestinal Caco-2 cells. MPP+ is a prototypic substrate of the cloned organic cation transporters hOCT1 and hOCT2. 2. In Caco-2 cell monolayers, the basolateral to apical flux of MPP+ was significantly greater than the apical to basolateral flux, consistent with net secretion of MPP+. 3. Net secretion of MPP+ was abolished by addition of either 10 microM cyclosporin A or 100 microM verapamil to the apical membrane. In contrast, secretion of MPP+ was unaffected by addition of either TEA (2 mM) or decynium-22 (2 microM) to either apical or basolateral membranes. These results suggest that MPP+ secretion is mediated primarily by P-glycoprotein located at the apical membrane. We found no evidence of a role for hOCT1 or hOCT2 in the secretion of MPP+. 4. In addition to net secretion of MPP+, we found evidence of a Na(+)-dependent MPP+ uptake mechanism at the apical membrane of Caco-2 cells. 5. Na(+)-dependent MPP+ uptake was sensitive to inhibition by the organic cations; decynium-22 (2 microM), TEA (2 mM) and cimetidine (5 mM) but not by carnitine, guanidine or proline. 6. These results suggest that net secretion of MPP+ across the apical membrane of Caco-2 cells is a function of the relative contributions of MPP+ secretion mediated by P-glycoprotein and MPP+ absorption mediated by a novel Na(+)-dependent transport mechanism.

1-Methyl-4-phenylpyridinium↗

PubMed2000

The organic cation transporter OCT2 mediates the uptake of beta-adrenoceptor antagonists across the apical membrane of renal LLC-PK(1) cell monolayers.

Previous studies have shown that beta-adrenoceptor antagonists may be substrates of organic cation transporters in kidney and lung. In this study we examined the transport of the beta-adrenoreceptor antagonists propranolol and metoprolol, in renal LLC-PK(1) cell monolayers. Experiments with BCECF (2', 7'-bis(2carboxyethyl)-5(6)-carboxyfluorescein) loaded LLC-PK(1) cell monolayers demonstrated that metoprolol and propranolol flux across the basolateral membrane was consistent with non-ionic diffusion. Flux across the apical membrane consisted of both non-ionic diffusion and the uptake of the cationic form of the beta-adrenoceptor antagonists. Uptake of the cationic form of metoprolol across the apical membrane was Na(+)-independent, electrogenic and sensitive to external pH. Furthermore, uptake was sensitive to inhibition by Decynium-22 and the organic cations TEA (tetraethylammonium) and MPP(+) (1-methyl 4-phenylpyridinium). These results, allied with the apical location of the uptake mechanism suggest that beta-adrenoceptor antagonists may be substrates for the organic cation transporter, OCT2. To confirm beta-adrenoceptor antagonists as substrates for OCT2, we demonstrate, in cells transiently transfected with an epitope tagged version of hOCT2 (hOCT2-V5):(1) Decynium-22 sensitive [(14)C]-propranolol uptake, (2) cis-inhibition of OCT2 by a range of beta-adrenoceptor antagonists and (3) metoprolol induced intracellular acidification.

Adrenergic beta-Antagonists↗

PubMed2000

Bradykinin regulation of salt transport across mouse inner medullary collecting duct epithelium involves activation of a Ca(2+)-dependent Cl(-) conductance.

The mechanism by which bradykinin regulates renal epithelial salt transport has been investigated using a mouse inner medullary renal collecting duct cell-line mIMCD-K2. Using fura-2 loaded mIMCD-K2 cells bradykinin (100 nM) has been shown to induce a transient increase in intracellular Ca(2+) via activation of bradykinin B2 receptors localized to both the apical and basolateral epithelial cell surfaces. In mIMCD-K2 epithelial cell-layers clamped in Ussing chambers, 100 nM bradykinin via apical and basolateral bradykinin B2 receptors stimulated a transient increase in inward short-circuit current (I:(sc)) of similar duration to the increase in intracellular Ca(2+). Replacements of the bathing solution Na(+) by the impermeant cation, N-methyl-D-glucamine and of Cl(-) and HCO(3)(-) by the impermeant anion gluconate at either the apical (no reduction) or basal bathing solutions (abolition of the response) are consistent with the bradykinin-stimulated increase in inward I:(sc) resulting from basal to apical Cl(-) (anion) secretion. Using the slow whole cell configuration of the patch-clamp technique, bradykinin was shown to activate a transient Cl(-) selective whole cell current which showed time-dependent activation at positive membrane potentials and time-dependent inactivation at negative membrane potentials. These currents were distinct from those activated by forskolin (CFTR), but identical to those activated by exogenous ATP and are therefore consistent with bradykinin activation of a Ca(2+)-dependent Cl(-) conductance. The molecular identity of the Ca(2+)-dependent Cl(-) conductance has been investigated by an RT - PCR approach. Expression of an mRNA transcript with 96% identity to mCLCA1/2 was confirmed, however an additional but distinct mRNA transcript with only 81% of the identity to mCLCA1/2 was identified.

Animals↗

PubMed2000

Functional significance of the isoforms of endothelin-converting enzyme-1.

The subcellular localization of endothelin-converting enzyme-1 (ECE-1) is a matter of some controversy, further complicated by the discovery of its multiple isoforms. ECE-1 is a critical enzyme in the biosynthesis of the potent vasoconstrictor peptide endothelin (ET), and, as such, represents a potential target for drug therapy in the control of disease states involving the ET system. Knowledge of the precise locations of the isoforms and their regulation would aid in the design of drugs to target specifically ECE-1. In this study, the subcellular localization and potential targeting pathways of the ECE-1 isoforms were investigated. Antipeptide antibodies were raised to the unique N-terminal sequence of ECE-1b and were then used in the investigation of its subcellular distribution. Mutagenesis of proposed targeting sequences within the cytoplasmic tails of the isoforms was carried out to determine their significance in subcellular localization.

Animals↗

PubMed1999

The global topography of Mars and implications for surface evolution.

Elevations measured by the Mars Orbiter Laser Altimeter have yielded a high-accuracy global map of the topography of Mars. Dominant features include the low northern hemisphere, the Tharsis province, and the Hellas impact basin. The northern hemisphere depression is primarily a long-wavelength effect that has been shaped by an internal mechanism. The topography of Tharsis consists of two broad rises. Material excavated from Hellas contributes to the high elevation of the southern hemisphere and to the scarp along the hemispheric boundary. The present topography has three major drainage centers, with the northern lowlands being the largest. The two polar cap volumes yield an upper limit of the present surface water inventory of 3.2 to 4.7 million cubic kilometers.

Evolution, Planetary↗

PubMed1999

Phosphorylated serine422 on tau proteins is a pathological epitope found in several diseases with neurofibrillary degeneration.

Neuronal inclusions with bundles of abnormal filaments made of tau polymers are found in numerous diseases with neurofibrillary degeneration. Tau proteins are the basic components of paired helical filaments (PHF) in Alzheimer's disease (AD), and are abnormally phosphorylated. A disease-specific phosphorylation site at serine422 was demonstrated on PHF, but not on tau proteins from biopsy-derived brain samples. In the present study, we report the characterization of a polyclonal antibody (988) against the serine422 phosphorylation site. By using biochemical and immunohistochemical methods, we confirmed that it is not found on tau proteins from biopsy- or autopsy-derived control samples, and we investigated the presence of this epitope on tau proteins in several neurodegenerative disorders, including AD, Down syndrome (DS), Guamanian amyotrophic lateral sclerosis/Parkinsonism-dementia complex (ALS/PDC), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), postencephalitic parkinsonism (PEP) and Pick's disease (PiD). By Western blotting, antibody 988 labeled the characteristic tau triplet (tau 55, 64, 69) in AD, DS, Guamanian ALS/PDC and PEP. PSP and CBD exhibited their typical tau doublet (tau 64, 69), whereas the doublet tau 55 and 64 was detected in PiD. In all of these neurodegenerative disorders, antibody 988 clearly labeled NFT and dystrophic neurites, as well as Pick bodies in PiD cases, whereas no staining was observed in control cases. These data indicate that phosphorylation of serine422 on tau proteins is a common feature among neurodegenerative disorders and is therefore not specific of AD. Moreover, phosphorylation of this epitope permits the distinction between normal tau proteins and pathological tau proteins.

Adult↗

PubMed1999

Early events in naphthalene-induced acute Clara cell toxicity: comparison of membrane permeability and ultrastructure.

Naphthalene causes severe dose- and site-selective injury to mouse nonciliated bronchiolar (Clara) epithelial cells. Toxicity is characterized by exfoliation of injured Clara cells into the airway lumen 24 h after exposure. The purpose of this study was to define the temporal pattern of intracellular changes immediately following naphthalene treatment, with the goal of identifying critical early events involved in cytotoxicity. Mice were injected with naphthalene or carrier and were killed 1, 2, 3, and 6 h after treatment (PT). Loss of membrane integrity was assessed by ethidium homodimer-1 permeability and confocal microscopy. Cell morphology and ultrastructure were evaluated using high-resolution light and electron microscopy. Permeable cells were found only in terminal bronchioles and increased in abundance with time PT. At 2 and 3 h PT, when most Clara cells had early signs of injury, few permeable cells were detected. Many Clara cells had apical membrane blebs that contained abundant, swollen, smooth endoplasmic reticulum (SER) and few other organelles. By 6 h PT many Clara cells were membrane-permeable. However, many permeable Clara cells lacked apical blebs and SER was less abundant in these cells. Cytoplasmic blebbing may be a mechanism to protect the cell by isolating and removing damaged SER. We conclude that the early stages of injury include SER swelling and bleb formation which precede increases in cell membrane permeability after acute naphthalene injury to bronchiolar Clara cells in vivo.

Animals↗

PubMed1999

Characterization of the analgesic and anti-inflammatory activities of ketorolac and its enantiomers in the rat.

The marked analgesic efficacy of ketorolac in humans, relative to other nonsteroidal anti-inflammatory drugs (NSAIDs), has lead to speculation as to whether additional non-NSAID mechanism(s) contribute to its analgesic actions. To evaluate this possibility, we characterized (R,S)-ketorolac's pharmacological properties in vivo and in vitro using the nonselective cyclooxygenase (COX) inhibitors [indomethacin (INDO) and diclofenac sodium (DS)] as well as the selective COX-2 inhibitor, celecoxib, as references. The potency of racemic (R,S)-ketorolac was similar in tests of acetic acid-induced writhing, carrageenan-induced paw hyperalgesia, and carrageenan-induced edema formation in rats; ID50 values = 0.24, 0. 29, and 0.08 mg/kg, respectively. (R,S)-ketorolac's actions were stereospecific, with (S)-ketorolac possessing the biological activity of the racemate in the above tests. The analgesic potencies for (R,S)-, (S)-, and (R)-ketorolac, INDO, and DS were highly correlated with their anti-inflammatory potencies, suggesting a common mechanism. (R,S)-ketorolac was significantly more potent than INDO or DS in vivo. Neither difference in relative potency of COX inhibition for (R,S)-ketorolac over INDO and DS nor activity of (S)-ketorolac at a number of other enzymes, channels, or receptors could account for the differences in observed potency. The distribution coefficient for (R,S)-ketorolac was approximately 30-fold less than for DS or INDO, indicating that (R,S)-ketorolac is much less lipophilic than these NSAIDs. Therefore, the physicochemical and pharmacokinetics properties of (R,S)-ketorolac may optimize the concentrations of (S)-ketorolac at its biological target(s), resulting in greater efficacy and potency in vivo.

Acetic Acid↗

PubMed1998

Anti-peptide antibodies specific to rat endothelin-converting enzyme-1 isoforms reveal isoform localisation and expression.

Endothelin-converting enzyme-1 (ECE-1) is a critical enzyme in the biosynthesis of the potent vasoconstrictor peptide endothelin and exists in several isoforms. Anti-peptide antibodies raised against epitopes in the distinct N-terminal cytoplasmic tails of the rat ECE-1 isoforms have been obtained. By using these antibodies in Western blot analysis and immunofluorescence studies, we have shown that cultures of transformed rat lung vascular endothelial cells treated with the metalloprotease inhibitor phosphoramidon and untreated cells express ECE-1alpha only, whereas human umbilical vein endothelial cells express ECE-1alpha and ECE-1beta. The ECE-1 isoforms expressed in CHO-K1 cells transfected with rat cDNA to ECE-1alpha and ECE-1beta could be immunoprecipitated by using the appropriate isospecific antibody.

Amino Acid Sequence↗

PubMed1998

Ethylene oxide dosimetry in the mouse.

Ethylene oxide (EO) is a direct-acting mutagen and animal carcinogen used as an industrial intermediate and sterilant with a high potential for human exposure. Understanding the exposure-dose relationship for EO in rodents is critical for developing human EO exposure-dose models. The study reported here examined the dosimetry of EO in male B6C3F1 mice by direct determination of blood EO concentrations. Steady-state blood EO concentrations were measured during a single 4-h nose-only inhalation exposure (0, 50, 100, 200, 300, or 400 ppm EO). In addition, glutathione (GSH) concentrations were measured in liver, lung, kidney, and testis to assess the role of the GSH depletion in the saturable metabolism previously observed in mice (Brown et al., Toxicol. Appl. Pharmacol. 136, 8-19, 1996). Blood EO concentrations were found to increase linearly with exposure concentration up to 200 ppm. Markedly sublinear blood dosimetry was observed at exposure concentrations exceeding 200 ppm. An EO exposure concentration-dependent reduction in tissue GSH levels was observed, with both liver and lung GSH levels significantly depressed at EO exposure concentrations of 100 ppm or greater. Our results also indicate that depletion of GSH is likely responsible for nonlinear dosimetry of EO in mice and that GSH depletion corresponds with reports of dose-rate effects in mice exposed to EO.

Administration, Inhalation↗

PubMed1997

Cardiovascular health risks related to overweight.

Cross-sectional surveys of the civilian noninstitutionalized population of the United States, including in-home interviews and clinical examinations, were employed to examine trends in consumption of energy and fat, prevalence of overweight in the population, the association of overweight with levels of blood pressure and blood cholesterol, and the prevalence of high blood pressure and high blood cholesterol among the overweight compared with the nonoverweight. Data from participants 20 years of age and older are reported. Study results suggest that total mean energy intake, although generally accepted to be underreported in dietary surveys, may have increased. Total fat and saturated fat intake as a percent of energy decreased, but remained above recommended levels. Overweight has increased in the population, despite decreases in the prevalence of high blood pressure and high blood cholesterol levels. Increased levels of overweight, reported as body mass index, are associated with increased cardiovascular risk factors of high blood pressure and high blood cholesterol. These data suggest the need for health care practitioners to emphasize the requirement for energy balance (or weight loss if overweight, ie, not at a "healthy weight"). A focus on fat intake alone without emphasis on energy balance is inadequate for achieving and maintaining recommended weight.

Adult↗

PubMed1997

Surgical margins for excision of primary cutaneous melanoma.

BACKGROUND: A major controversy in the treatment of melanoma is the width of the surgical margin necessary for complete excision. Although surgical margins have decreased in recent years, the current recommendations are mainly based on arbitrary choices, only two of which have been tested in clinical trials. OBJECTIVE: Our purpose was to use prospective data, measuring the extent of subclinical melanoma extensions, to develop guidelines for predetermined surgical margins for the excision of cutaneous melanoma. METHODS: A prospectively collected series of 535 patients with 553 primary cutaneous melanomas was studied. All melanomas were excised by means of the fresh tissue technique of Mohs micrographic surgery with frozen section examination of the margin. The surgical margin needed for excision of melanoma was determined by measuring the invisible extensions of tumor around the melanoma. The minimum surgical margin was 6 mm and the total margin was calculated by adding an additional 3 mm for any melanoma requiring a subsequent stage to remove the tumor completely. RESULTS: Eighty-three percent of melanomas were successfully excised with a 6 mm margin; 9 mm removed 95% of the melanomas; and a 1.2 cm margin was necessary to remove 97% of all melanomas. Margins to remove melanomas on the head, neck, hands, and feet were wider than those on the trunk and extremities. Margins to remove melanomas that were more than 2 to 3 cm in diameter were wider than for smaller melanomas. CONCLUSION: Predetermined surgical margins for excision of melanoma or melanoma in situ by standard surgical techniques should include 1 cm of normal-appearing skin for melanomas on the trunk and proximal extremities that are smaller than 2 cm in diameter, or a 1.5 cm margin for tumors larger than 2 cm in diameter. For melanomas on the head, neck, hands, and feet, a minimum surgical margin of 1.5 cm is recommended or a margin of 2.5 cm for melanomas larger than 3 cm in diameter. Mohs micrographic surgery is a useful alternative to standard surgery when more narrow margins are desired, particularly for melanomas on the head, neck, hands, and feet, or melanomas larger than 2.5 cm in diameter, or for melanomas without distinct clinical margins.

Humans↗

PubMed1997

Osteochondritis dissecans of the patella: arthroscopic fixation with bioabsorbable pins.

Osteochondritis dissecans of the patella is a relatively rare condition. Surgical treatment has been recommended for those patients who fail conservative treatment, or who present with mechanical symptoms or loose bodies. In an attempt to preserve the patellofemoral articulation, we describe a new technique to arthroscopically fix osteochondritic lesions of the patella using bioabsorbable pins. This technique avoids the morbidity of a formal arthrotomy as well as the complications associated with metallic hardware.

Arthroscopy↗

PubMed1996

In vivo and in vitro kinetics of ethylene oxide metabolism in rats and mice.

Ethylene oxide (EO) is a direct-acting mutagen and animal carcinogen used as an industrial intermediate and sterilant with a high potential for human exposure. Kinetics of EO metabolism in rodents can be used to develop human EO dosimetry models. This study examined the kinetics of EO metabolism in vivo and in vitro in male and female F-344 rats and B6C3F1 mice. In vivo studies measured blood and tissue EO levels during and 2-20 min following whole-body inhalation exposure (4 hr, 100 or 330 ppm EO). At 100 ppm EO, the half-life of elimination (t1/2) in rats was 13.8 +/- 0.3 (mean +/- SD) and 10.8 +/- 2.4 min for males and females, respectively, compared to a t1/2 in mice of 3.12 +/- 0.2 and 2.4 +/- 0.2 min in males and females, respectively. On exposure to 330 ppm EO, the t1/2 in mice increased approx twofold, while no change in t1/2 was observed in rats. In vitro kinetic parameters (Vmax and KM) of EO metabolism were determined using tissue cytosol and microsomes. EO metabolism in vitro occurred primarily via cytosolic glutathione S-transferase-mediated EO-GSH conjugation (cGST-EO), with highest activity in the liver. Liver cGST-EO activity (Vmax) was 258 +/- 86.9 and 287 +/- 49.0 nmol/mg protein/min (mean +/- SD) in male and female mice, respectively, compared to 52.7 +/- 10.8 and 29.3 +/- 4.9 in male and female rats, respectively. In rats, but not mice, there was a statistically significant (p < 0.05) gender difference in the Vmax for liver cGST. The KM for liver cGST-EO was approximately 10 mM in both species. The higher Vmax values observed in mice are consistent with the more rapid elimination of EO observed for this species in vivo compared to rats.

Administration, Inhalation↗

PubMed1996

Chloride channel blockers decrease intracellular pH in cultured renal epithelial LLC-PK1 cells.

The effects of chloride channel blockers upon intracellular pH (pHi) were examined in renal epithelial monolayers of LLC-PK1 cells. A significant intracellular acidification was found with addition of 100 microM 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB), niflumic acid, flufenamate and diphenylamine-2-carboxylate (DPC) but not with 4,4'-diisothiocyanatostilbene-2-2'disulphonic acid (DIDS). The effects of these agents upon pHi was dose-dependent with apparent K0.5 values of: 16.7 +/- 0.3 microM, 34.2 +/- 0.9 microM and 740 +/- 13 microM for niflumic acid, flufenamate and DPC respectively. The results indicate that at concentrations commonly used to block channel activity these chloride channel blockers have profound effects upon pHi.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed1996

Mediation of cimetidine secretion by P-glycoprotein and a novel H(+)-coupled mechanism in cultured renal epithelial monolayers of LLC-PK1 cells.

1. Previous studies have shown that the weak base, cimetidine, is actively secreted by the renal proximal tubule. In this study we have examined the transport of cimetidine by renal LLC-PK1 epithelial cell monolayers. 2. In LLC-PK1 cell monolayers the basal-to-apical flux of cimetidine was significantly greater than the apical-to basal flux, consistent with net secretion of cimetidine in a basal-to-apical direction. 3. Net secretion of cimetidine was significantly (70%) reduced by the addition of either 100 microM verapamil or 100 microM nifedipine to the apical membrane. The reduction in net secretion was the result of an inhibition of basal-to-apical flux; these agents had no effect upon flux in the apical-to-basal direction. These results suggest that cimetidine secretion is mediated primarily by P-glycoprotein located in the apical membrane. In addition we found no evidence of a role for organic cation antiport in the secretion of cimetidine. 4. In the presence of an inwardly directed proton gradient across the apical membrane (pH 6.0), cimetidine secretion was significantly reduced compared to that measured at an apical pH of 7.4. The reduction in net secretion at pH 6.0 was the result of a stimulation of cimetidine uptake across the apical membrane. This pH-dependent uptake mechanism was sensitive to inhibition by DIDS (100 microM). 5. Experiments with BCECF (2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein) loaded monolayers demonstrated that cimetidine influx across the apical membrane was associated with proton flow into the cell and was sensitive to inhibition by DIDS. 6. These results suggest that net secretion of cimetidine across the apical membrane is a function of the relative magnitudes of cimetidine secretion mediated by P-glycoprotein and cimetidine absorption mediated by a novel proton-coupled, DIDS-sensitive transport mechanism.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed1995

Isolated systolic and diastolic ventricular interactions in pacing-induced dilated cardiomyopathy and effects of volume loading and pericardium.

BACKGROUND: Interactions between the closely coupled right and left ventricles are known to play important roles as determinants of ventricular function, and the purpose of this study was to evaluate their effects in a model of heart failure. METHODS AND RESULTS: A dilated cardiomyopathy resulting in congestive heart failure (CHF) was produced in pigs by rapid ventricular pacing at 230 beats per minute for 1 week. Blood was rapidly withdrawn from the left ventricular (LV) apex into a prosthetic ventricle, and the instantaneous effects on the right ventricle were studied during volume loading and before and after pericardiectomy. The systolic interaction gain between the right and left ventricles (Gs) was calculated as the ratio of changes in mean systolic pressure during isolated systolic LV unloading. Diastolic ventricular interaction gain (Gd) was calculated as the ratio of changes in mean diastolic pressures during LV unloading in the last 150 ms of diastole. With the pericardium closed, all interaction gains were significantly increased during volume loading from a right ventricular end-diastolic pressure of 3 to 9 mm Hg: Gs from 0.045 +/- 0.014 to 0.063 +/- 0.020 mm Hg/mm Hg (normal pigs) and from 0.077 +/- 0.040 to 0.103 +/- 0.019 (CHF pigs) and Gs from 0.196 +/- 0.116 to 0.493 +/- 0.117 mm Hg/mm Hg (normal pigs) and from 0.174 +/- 0.101 to 0.341 +/- 0.165 (CHF pigs). When the pericardium was opened, Gd was significantly reduced to 0.145 +/- 0.071 and 0.129 +/- 0.026 mm Hg/mm Hg (normal and CHF pigs, respectively), but Gs showed no significant change (0.067 +/- 0.027 and 0.109 +/- 0.012 mm Hg/mm Hg for normal and CHF pigs, respectively), and both were also significantly increased during volume loading. Gs was significantly greater in CHF versus normal pigs under all conditions, but there were no differences in Gd between CHF and normal pigs. CONCLUSIONS: These results suggest that dilated cardiomyopathy increases systolic but not diastolic interactions, that the pericardium increases diastolic but not systolic ventricular interactions, and that volume loading with and without the pericardium opened increases both systolic and diastolic interactions.

Animals↗

PubMed1995

Metabolism and testicular toxicity of 1,3-dinitrobenzene in the rat: effect of route of administration.

Studies investigating the testicular toxicity of 1,3-dinitrobenzene (1,3-DNB) have utilized both the oral (po) and intraperitoneal (ip) routes of administration. These two administration routes could be expected to produce different pharmacokinetic profiles and, potentially, different degrees of toxicity. In the present work, the effect of route of administration upon 1,3-DNB disposition and susceptibility to testicular damage has been investigated. Male Sprague-Dawley rats were given 25 mg/kg 1,3-DNB either ip or po. Metabolites were quantitated in blood, urine, and feces, and methemoglobin levels were determined. Peak blood levels of 1,3-DNB and its major metabolite were three times higher in ip-dosed rats than in po-dosed rats. While the lower blood levels seen after po administration were maintained for greater than 6 hr, blood levels fell rapidly after ip dosing, reaching po levels at 6 hr postadministration. Peak methemoglobin levels in ip-dosed animals were twice that of po-dosed animals. Route of administration had a minor effect on the levels of urinary metabolites, while there was a significantly higher excretion of metabolites in the feces of po-dosed animals. Despite the markedly higher 1,3-DNB blood levels after ip administration, there were only subtle differences in testicular damage. The data raise the possibility that above a threshold level of 1,3-DNB in the blood, only the duration of testicular exposure to the toxicant may govern susceptibility to testicular toxicity.

Administration, Oral↗