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Biomedical subjects

J Odum

Publications and source records attributed to J Odum.

49 records · Page 3Linked to original sources
PubMed1992

A mechanism for the development of Clara cell lesions in the mouse lung after exposure to trichloroethylene.

Female CD-1 mice exposed to trichloroethylene (6 h/day) at concentrations from 20-2000 ppm developed a highly specific lung lesion after a single exposure, characterised by vacuolation of the Clara cells, the number of cells affected increasing with increasing dose level. At the highest dose levels pyknosis of the Clara cells was apparent. After 5 days of repeated exposures the lesion had resolved but exposure of mice following a 2-day break resulted in recurrence of the lesion. The changes in mouse lung Clara cells were accompanied by a marked loss of cytochrome P-450 activities. No morphological changes were seen in the lungs of rats exposed to either 500 or 1000 ppm trichloroethylene. Isolated mouse lung Clara cells were shown to metabolize trichloroethylene to chloral, trichloroethanol and trichloroacetic acid. Chloral was the major metabolite. Trichloroethanol glucuronide was not detected. In comparative experiments using mouse hepatocytes the major metabolites were trichloroethanol and its glucuronide conjugate. The activity of UDP-glucuronosyltransferase was compared in mouse lung Clara cells and hepatocytes using two phenolic substrates and trichloroethanol. Hepatocytes readily formed glucuronides from all three substrates whereas Clara cells were only active with the two phenolic substrates. The three major metabolites of trichloroethylene, chloral, trichloroethanol and trichloroacetic acid were each dosed to mice and of these metabolites, only chloral had an effect on mouse lung causing a lesion (Clara cell) identical to that seen with trichloroethylene. It is proposed that the failure of Clara cells to conjugate trichloroethanol leads to an accumulation of chloral which results in cytotoxicity. The known genotoxicity of chloral suggests that this lesion may be related to the development of lung tumours in mice exposed to trichloroethylene by inhalation.

Animals↗
PubMed1991

Congestive heart failure and converting enzyme inhibition: failure of current prognostic criteria for predicting subsequent renal insufficiency.

Angiotensin-1-converting enzyme inhibitors have an effective and established role in the treatment of patients with congestive heart failure. However, a small number of such patients will subsequently develop renal insufficiency. These patients may be identified prior to, or shortly after, commencement of therapy by recognized criteria. This report describes 4 patients with congestive heart failure who developed severe renal insufficiency secondary to either enalapril or captopril therapy in the absence of any currently recognized predisposing factors. One patient died.

Aged↗
PubMed1990

Perchloroethylene-induced rat kidney tumors: an investigation of the mechanisms involved and their relevance to humans.

Lifetime exposure to perchloroethylene by inhalation has been shown to cause a low incidence of renal tumors in male rats. The mechanisms responsible for the induction of these tumors have been investigated following exposure of rats to perchloroethylene by oral gavage (1500 mg/kg for up to 42 days) or by inhalation (400 ppm for 28 days). Comparisons have been made between rats and mice in vivo and between rats, mice, and humans in vitro. High doses of perchloroethylene given by gavage have been shown to be toxic to the rat kidney, causing increases in urinary markers of kidney damage. A marked accumulation of protein droplets (alpha-2u-globulin) was seen in the P2 segment of the kidney proximal tubules. This response were not seen after inhalation exposure to 400 ppm perchloroethylene for 28 days and hence may not be associated with the tumors seen at this dose level. Protein droplet formation was seen after exposure to 1000 ppm perchloroethylene, suggesting that 400 ppm is below the threshold dose required to induce this response. Perchloroethylene has been shown to be metabolized by glutathione conjugation in the liver, resulting in the formation of a mutagenic cysteine conjugate which is activated by the kidney enzyme beta-lyase. Levels of the mercapturic acid of perchloroethylene have been compared in rat and mouse urine. The enzyme kinetics of hepatic glutathione conjugation and renal beta-lyase activation have been compared in rat, mouse, and human tissues in vitro. Results of these studies are consistent with the rat being the species susceptible to kidney tumors. Although human kidney was shown to contain beta-lyase, glutathione conjugation of perchloroethylene could not be detected in human liver. Perchloroethylene-induced male rat kidney tumors may be a result of chronic toxicity, protein droplet nephropathy, and genotoxicity from the beta-lyase pathway. These mechanisms appear to have little relevance to humans.

Administration, Inhalation↗
PubMed1988

The role of trichloracetic acid and peroxisome proliferation in the differences in carcinogenicity of perchloroethylene in the mouse and rat.

Fischer 344 rats and B6C3F1 mice of both sexes were exposed to 400 ppm perchloroethylene (PER) by inhalation, 6 hr/day for 14, 21, or 28 days or to 200 ppm for 28 days. Increased numbers of peroxisomes were seen under the electron microscope and increased peroxisomal cyanide-insensitive palmitoyl CoA oxidation was measured (3.6-fold increase in males and 2.1-fold increase in females) in the livers of mice exposed to PER. Hepatic catalase was not increased. Peroxisome proliferation was not observed in rat liver or in the kidneys of either species. Trichloracetic acid (TCA), a known carcinogen and hepatic peroxisome proliferating agent, was found to be a major metabolite of PER. Blood levels of this metabolite measured in mice and rats during and for 48 hr after a single 6-hr exposure to 400 ppm PER showed that peak blood levels in mice were 13 times higher than those seen in rats. Comparison of areas under the curves over the time course of the experiment showed that mice were exposed to 6.7 times more TCA than rats. The difference in metabolism of PER to TCA in mice and rats leads to the species difference in hepatic peroxisome proliferation which is believed to be the basis of the species difference in hepatocarcinogenicity. Peroxisome proliferation does not appear to play a role in the apparent carcinogenicity of PER in the rat kidney.

Administration, Inhalation↗
PubMed1986

Transport of N-acetyl-S-pentachloro-1,3-butadienylcysteine by rat renal cortex.

N-acetyl-S-pentachloro-1,3-butadienyl-L-cysteine (PCBD-NAC) is a postulated metabolite derived from glutathione conjugation of hexachloro-1,3-butadiene and is nephrotoxic in the rat. Because PCBD-NAC causes selective necrosis to the pars recta of the proximal tubule, and is an organic anion it might be expected to be transported by the renal organic anion transport system. Rat renal cortical slices were used to characterise the transport. 14C-PCBD-NAC uptake was temperature dependent and reduced by the metabolic inhibitors cyanide and iodoacetate. Probenecid and sulphinpyrazone, specific competitive inhibitors of the anion transport system, and dinitrophenol, a metabolic inhibitor as well as a competitive inhibitor of anion transport, reduced PCBD-NAC transport. Organic cations or uric acid transport inhibitors did not alter PCBD-NAC accumulation by the slices. These data are consistent with the transport of PCBD-NAC by the renal organic anion secretory system.

Acetylcysteine↗
PubMed1985

Structure/activity studies of the nephrotoxic and mutagenic action of cysteine conjugates of chloro- and fluoroalkenes.

The cysteine conjugates of the nephrotoxins hexachlorobutadiene (HCBD), tetrafluoroethylene (TFE) and hexafluoropropene (HFP), together with those of trichloroethylene and perchloroethylene, have been chemically synthesized and a relationship determined between their structures and their nephrotoxicity and mutagenicity in vitro. All of the conjugates had a marked effect on the uptake of both the organic anion p-aminohippuric acid (PAH) and the cation tetraethylammonium bromide (TEA) into rat kidney slices, suggesting activation of the conjugates in the slices to a toxic species which interferes with ion transport. This observation is consistent with the known nephrotoxicity of HCBD, TFE and HFP in vivo. Each of the conjugates was found to be metabolised by rat kidney slices and by semi-purified rat kidney beta-lyase to pyruvate, ammonia and an unidentified reactive metabolite. When semi-purified beta-lyase was used stoichiometric amounts of pyruvate and ammonia were produced. Although all of the conjugates were activated by beta-lyase and had a similar effect on ion transport their mutagenicity differed markedly. The conjugates of HCBD, trichloroethylene and perchloroethylene were mutagenic in the Ames bacterial mutation assay when activated by rat kidney S9. Metabolic cofactors were not required suggesting that activation was due to the enzyme beta-lyase. In the same assay the conjugates of TFE and HFP were not mutagenic either in the presence or absence of rat kidney S9 and cofactors. With a limited number of cysteine conjugates a clear distinction has been identified between the conjugates of chloroalkenes which were were similarly nephrotoxic but were not mutagenic. The mutagenicity of the cysteine conjugate of HCBD is consistent with the known renal carcinogenicity of this chemical.

Alkenes↗
PubMed1984

The metabolism and nephrotoxicity of tetrafluoroethylene in the rat.

Exposure of rats to 6000 ppm tetrafluoroethylene for 6 hr produced marked damage to the proximal tubule of the kidney with no effect on the liver. The toxicity was characterized by very high concentrations of urinary glucose and by marked increases in the concentrations of several urinary enzymes. The no observed effect level for a 6-hr exposure was 2000 ppm. Tetrafluoroethylene was metabolized to S-(1,1,2,2-tetrafluoroethyl)glutathione by rat liver fractions in vitro; the reaction was catalyzed by both microsomal and cytosolic glutathione S-transferases. The rate with microsomes was four times that with cytosol fractions. Evidence for this metabolic pathway in vivo has been obtained by the identification of the cysteinylglycine and cysteine conjugates of tetrafluoroethylene in rat bile. Cytochrome P-450 oxidation, a common metabolic route for haloalkenes, does not appear to occur in the metabolism of tetrafluoroethylene. When administered po to rats, the synthetic cysteine conjugate of tetrafluoroethylene causes renal damage identical to that caused by tetrafluoroethylene itself. The conjugate was metabolized by renal slices in vitro giving pyruvate, ammonia, and a reactive species which caused marked inhibition of organic ion transport into slices. Purified renal beta-lyase also cleaved this conjugate giving stoichiometric amounts of pyruvate and ammonia. The nephrotoxicity of tetrafluoroethylene is believed to derive from the hepatic glutathione conjugate of this compound. Following excretion and degradation of this conjugate in bile, the cysteine conjugate is reabsorbed and further metabolized in the kidney by the enzyme beta-lyase to a cytotoxic species.

Animals↗
PubMed1983

Hepatic microsomal glucuronidation of clofibric acid in the adult and neonate albino rat.

Hepatic microsomal UDP glucuronyltransferase activity towards the acid substrate clofibric acid has been described in the adult and neonate albino rat. The enzyme was maximally activated, approximately 2-fold, in the presence of 0.1-0.4% (w/v) digitonin. Induction of the digitonin activated clofibric acid glucuronyltransferase was observed following phenobarbitone treatment in vivo (2.2-fold), and to a lesser extent, following beta-naphthoflavone treatment (1.3-fold). Clofibrate treatment in vivo (of which clofibric acid is the ester hydrolysis product) had no effect on clofibric acid glucuronidation in vitro. The activity of clofibric acid glucuronyltransferase in the liver of rat before and at birth was low (approx. 0.08 nmoles glucuronide formed/min/mg microsomal protein). The activity increased 5-fold during the first three post-natal days. After this time, the activity increased linearly reaching adult levels by four weeks after birth. The data indicated that clofibric acid glucuronyltransferase belongs to the neonatal cluster of enzymes and clofibric acid is a group 2 substrate. Clofibric acid, a common therapeutic agent, is a useful, acid substrate for the estimation of mammalian hepatic microsomal glucuronyltransferase activity.

Aging↗
PubMedDate not supplied

Effects of p-nonylphenol (NP) and diethylstilboestrol (DES) on the Alderley Park (Alpk) rat: comparison of mammary gland and uterus sensitivity following oral gavage or implanted mini-pumps.

An earlier report by Colerangle and Roy indicated that administration of p-nonylphenol (NP) to Noble rats, via subcutaneously implanted mini-pumps at estimated doses of 53.2 and 0.073 mg kg(-1) day(-1) for 11 days, led to proliferation of the mammary gland. Those results indicated a ca. 600-fold enhancement in assay sensitivity to NP over that of the standard 3-day rat uterotrophic assay. The potential importance of these observations led us to repeat the experiments in the Noble rat, as described earlier. Although our earlier results confirmed the reported effects of diethylstilboestrol (DES) on the mammary gland of Noble rats, we found no effects with NP. The present report extends our investigations of the effects of NP and DES on the mammary gland and uterus of other rat strains using both oral dosing and exposure via mini-pumps. The 3-day oral uterotrophic assay responses to NP were similar for immature Alderly Park (Alpk; Wistar-derived) and immature Sprague-Dawley rats. Likewise, oral administration of NP to ovariectomized Alpk rats for 11 days gave responses of a similar magnitude to those seen in the 3-day immature assays and in earlier 3-and 11-day oral assays conducted using Noble rats. Administration of NP via mini-pumps to ovariectomized Alpk rats, at the implant doses employed by Colerangle and Roy, gave a negative uterotrophic response. The highest achieved dose levels of NP in the implant experiment (27 mg kg(-1) day(-1)) were lower than in the above assays and the negative response was therefore consistent with the previously defined minimum detection level for NP in the uterotrophic assay of ca. 40 mg kg(-1) day(-1) day(-1). It is concluded that the uterotrophic activity of NP is independent of the strain of rat, the duration of dosing and the route of exposure. Two mammary gland studies were conducted on NP and DES in the Alpk rat. In the first study (a repeat of the techniques used in earlier studies with the Noble rat), NP was administered via mini-pumps (achieved doses of 0.052 and 37.4 mg kg(-1) day(-3) NP) and produced no effect on mammary gland development, whereas DES gave the expected trophic response. In the second mammary gland study, NP was administered orally to Alpk rats at 100 mg kg(-1) day(-1) for 11 days (a dose that produced a positive uterotrophic response in ovariectomized rats). In this experiment, DES, and to a lesser extent NP, increased mammary gland differentiation and cell proliferation. The present studies have demonstrated that the rat mammary gland responds predictably to oestrogenic stimulation but does not show increased sensitivity to oestrogens when compared to the rat uterus. It is also concluded that the minimum detection level for oestrogenic responses of NP in rodents, following oral, dietary and implant routes of exposure, is ca. 40 mg kg(-1) day(-1).

Administration, Oral↗