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Biomedical subjects

E A Lock

Publications and source records attributed to E A Lock.

At least 109 records · Page 6Linked to original sources
PubMed1986

Alpha 2U-globulin: measurement in rat kidney following administration of 2,2,4-trimethylpentane.

Hyaline droplet formation was stimulated markedly in the kidneys of post-puberty male rats 24-48 h after a single oral dose of 12/24 mmol/kg 2,2,4-trimethylpentane [TMP]. Renal hyaline droplet formation could not be detected in female rats or in pre-puberty male rats following similar doses of TMP. A dose-dependent increase in the renal concentration of the androgen-dependent low molecular weight protein, alpha 2U-globulin was observed in post-puberty male rats 24 h after a single oral dose of TMP, over the range 0.3-12.0 mmol/kg. After administration of a single dose of 12 mmol/kg TMP to male rats, the renal concentration of alpha 2U-globulin rose steadily up to a peak after 48 h and then returned slowly to near normal after 7 days. Renal alpha 2U-globulin could not be detected in female rats and in pre-puberty male rats. An immunocytochemical assay was developed to examine the distribution of alpha 2U-globulin within the kidney. alpha 2U-Globulin was localised primarily in the S2 segment of renal proximal tubules in untreated male rats. Rats which received a single dose of 12 mmol TMP/kg showed not only a greater staining intensity, due to the presence of a higher concentration of alpha 2U-globulin, but also staining in adjacent segments of the renal cortex. Several urinary biochemical indicators of nephrotoxicity were measured daily in male rats for up to 72 h following a single dose of 12 mmol TMP/kg. Renal proximal tubular function was unimpaired by TMP treatment. On the basis of studies in untreated and TMP-treated rats, a strong association has been found between the presence of renal hyaline droplets and the occurrence of renal alpha 2U-globulin. The findings in the present study provide an explanation for the occurrence of renal hyaline droplets only in adult male rats, but do not, as yet, establish the toxicological significance of increases in renal hyaline droplet formation.

Alpha-Globulins↗
PubMed1986

Nephrotoxicity of hexachlorobutadiene and its glutathione-derived conjugates.

The nephrotoxicity of hexachloro-1,3-butadiene (HCBD), its glutathione conjugate (HCBD-GSH), cysteine conjugate (HCBD-CYS), and its N-acetyl cysteine conjugate (HCBD-NAC) were compared in male and female Alderley Park rats. Rats, six to eight weeks of age, were given a single intra-peritoneal injection of HCBD or its conjugates and killed 24 hours later. Nephrotoxicity was assessed by histological examination and plasma urea. All three glutathione-derived conjugates produced an elevation of plasma urea and proximal renal tubular necrosis with a similar localization in the pars recta as seen with HCBD. All the conjugates were more nephrotoxic than HCBD itself. HCBD was about four times more toxic to female rats than males. This sex difference was also shown by all the HCBD metabolites.

Acetylcysteine↗
PubMed1985

A monoclonal antibody raised to rat liver cytochrome P-448 (form C) which recognises an epitope common to many other forms of cytochrome P-450.

A murine monoclonal antibody has been raised against a partially purified preparation of hepatic cytochrome P-448 (form c) from beta-naphthoflavone-treated rats. The monoclonal origin of the antibody was established by limiting dilution culture and isoelectricfocusing. The antibody has been designated 3/4/2. It reacts with apparently homogeneous cytochrome P-448 from rat liver in solid phase assay. It also cross reacts with a number of other cytochromes P-450, from rat and rabbit. In addition, a positive reaction was obtained with microsomal fractions from a variety of species, including man. None of the species tested was negative. The antibody does not react appreciably with purified haemoproteins other than cytochromes P-450. Antibody 3/4/2 is not inhibitory, either in reconstituted systems or with intact microsomal fraction. However, evidence was obtained that the antibody does cause some perturbation of the tertiary structure of the apoprotein at or near the haem.

Animals↗
PubMed1985

Hexachloro-1,3-butadiene-induced hydropic change in mouse liver.

Hexachloro-1,3-butadiene (HCBD) produced a time- and dose-related increase in hepatic water content following i.p. administration to male Alderley Park (Alpk/AP) mice. The increase in liver water was maximal 1-2 days after a single dose of 50 mg kg-1 and had returned to normal by day 5. Associated with the increased water, there was a parallel increase in Na+ and K+ ions, with no overall change in intracellular cation concentration. Liver non-protein sulphydryl content showed no consistent time-related decrease after 50 mg kg-1 HCBD. Histopathological examination of the liver showed fine cytoplasmic vacuolation of periportal hepatocytes which was more marked following 100 or 200 mg kg-1 than 50 mg kg-1 HCBD. In one animal, following 200 mg kg-1 HCBD, the liver showed ballooning and degeneration of periportal hepatocytes. Ultrastructural changes were evident 4 h after 50 mg kg-1 and consisted of mitochondrial swelling in periportal hepatocytes, whilst pericentral hepatocytes appeared normal. By 16 h, marked mitochondrial swelling and some proliferation of smooth endoplasmic reticulum were evident in periportal hepatocytes. Male mice of the C57BL/10J and C3H strains appeared to be more sensitive to HCBD-induced hepatic hydropic change than did the male and female Alpk/AP strain and male Balbc and DBA/2J strains. It appears that HCBD or a metabolite causes disruption of mitochondria in periportal hepatocytes which results in an influx of water and ions into the cell without compromising the Na+ pump.

Animals↗
PubMed1985

The metabolism of di(2-ethylhexyl) phthalate (DEHP) and mono-(2-ethylhexyl) phthalate (MEHP) in rats: in vivo and in vitro dose and time dependency of metabolism.

This study investigated the in vivo metabolism of di(2-ethylhexyl) phthalate (DEHP) and mono(2-ethylhexyl) phthalate (MEHP) in rats after multiple dosing, the metabolism of MEHP in primary rat hepatocyte cultures for periods of up to 3 days, and the biotransformation of some major metabolites of MEHP. Rats were orally administered [14C]DEHP or [14C]MEHP at doses of 50 and 500 mg/kg body wt for three consecutive days. Urine was collected at 24-hr intervals, and metabolite profiles were determined. After a single dose of either compound, urinary metabolite profiles were similar to those previously reported. However, after multiple administration of both DEHP and MEHP at 500 mg/kg, increases in omega-/beta-oxidation products [metabolites I and V, mono(3-carboxy-2-ethylpropyl) phthalate and mono(5-carboxy-2-ethylpentyl) phthalate, respectively] and decreases in omega - 1-oxidation products [metabolites VI and IX, mono(2-ethyl-5-oxohexyl) phthalate and mono(2-ethyl-5-hydroxyhexyl) phthalate, respectively] were seen. At the low dose of 50 mg/kg little or no alteration in urinary metabolite profiles was observed. At 500 mg/kg of MEHP a 4-fold stimulation of CN- -insensitive palmitoyl-CoA oxidation (a peroxisomal beta-oxidation marker) was seen after three consecutive daily doses. At the low dose of 50 mg/kg only a 1.8-fold increase was noted. Similar observations were made with rat hepatocyte cultures. MEHP at concentrations of 50 and 500 microM was extensively metabolized in the rat hepatocyte cultures. Similar metabolic profiles to those seen after in vivo administration of MEHP were observed. At the high (500 microM) concentration of MEHP, changes in the relative proportions of omega- and omega- 1-oxidized metabolites were seen. Over the 3-day experimental period, omega-/beta-oxidation products increased in a time-dependent manner at the expense of omega - 1-oxidation products. At a concentration of 500 microM MEHP, a 12-fold increase of CN- -insensitive palmitoyl CoA oxidation (a peroxisomal beta-oxidation marker) was observed. At the low concentration of MEHP (50 microM) only a 3-fold increase in CN- -insensitive palmitoyl-CoA oxidation was noted and little alteration in the metabolite profile of MEHP was observed with time. Biotransformation studies of the metabolites of MEHP confirmed the postulated metabolic pathways. Metabolites I and VI appeared to be endpoints of metabolism, while metabolite V was converted to metabolite I, and metabolite IX to metabolite VI. It was also possible to reduce the transformation of metabolite X [mono(2-ethyl-6-hydroxyhexyl) phthalate] to metabolite V.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1985

Effect of the organic acid transport inhibitor probenecid on renal cortical uptake and proximal tubular toxicity of hexachloro-1,3-butadiene and its conjugates.

Hexachloro-1,3-butadiene (HCBD), its glutathione conjugate (HCBD-GSH), cysteine conjugate (HCBD-CYS), and mercapturic acid derivative (HCBD-NAC) all produce acute necrosis of the pars recta of the proximal renal tubule in the rat. Previous studies have shown that radiolabel from administered HCBD appears to concentrate in the pars recta region. Renal uptake of radioactivity from HCBD-NAC was studied in rats by giving a single ip injection of the chemical and measuring its concentration in plasma and renal cortex 4 hr later. Cortex/plasma ratios (C/P) of HCBD-NAC were 4.35 +/- 0.21 (8 animals) at a dose of 64 mumol/kg and 10.4 +/- 0.55 (5) at a dose of 16 mumol/kg. These ratios were greater than that of inulin [C/P inulin = 1.5 +/- 0.2 (4)]. Thus cortical HCBD-NAC content was significantly greater than can be accounted for by glomerular filtration alone. Prior administration of probenecid (500 mumol/kg), a competitive inhibitor of organic acid transport, to animals receiving 16 or 64 mumol/kg of HCBD-NAC reduced the C/P to 1.03 +/- 0.09 (5) and 0.81 +/- 0.05 (8), respectively. Administration of probenecid in increasing doses (100, 200, 300, and 400 mumol/kg) to animals receiving 64 mumol/kg HCBD-NAC resulted in decreases of the C/P (2.59, 2.29, 1.35, and 0.84, respectively), suggesting a competitive inhibition of cortical HCBD-NAC uptake. The extent of covalently bound radioactivity from 64 mumol/kg HCBD-NAC was significantly greater in the renal cortex (1.11 +/- 0.2 nmol eq/mg protein) than in the liver (0.19 +/- 0.01 nmol eq/mg protein). Prior administration of probenecid (500 mumol/kg) reduced the renal cortical concentration of HCBD-NAC to 0.25 +/- 0.02 nmol eq/mg protein. Increasing doses of probenecid resulted in a progressive decrease in renal cortical covalent binding. When treatment with probenecid led to renal cortical concentrations of less than 120 nmol eq HCBD-NAC/g and an amount of covalently bound material less than 0.4 nmol eq/mg protein the animals were completely protected against the nephrotoxicity, as assessed by plasma urea and histopathological examination 24 hr after dosing. Prior administration of probenecid (500 mumol/kg) also protected rats against the nephrotoxicity produced by HCBD (192 mumol/kg), HCBD-GSH (47 mumol/kg), and HCBD-CYS (36 mumol/kg). It is suggested that the renal cortical accumulation and selective proximal tubular toxicity of HCBD and its conjugates is related to a carrier-mediated transport system.

Animals↗
PubMed1984

The metabolism and disposition of hexachloro-1:3-butadiene in the rat and its relevance to nephrotoxicity.

Following po administration of a nephrotoxic dose (200 mg/kg) of hexachloro-1:3-butadiene (HCBD) to male rats, the principal route of excretion was biliary, 17-20% of the dose being eliminated on each of the first 2 days. Fecal excretion over this period was less than 5% of the dose per day, suggesting enterohepatic recirculation of biliary metabolites. Urinary excretion was small, not exceeding 3.5% of the dose during any 24-hr period. The major biliary metabolite was a direct conjugate between glutathione and HCBD itself. The cysteinylglycine conjugate of HCBD has also been found in bile. Evidence was obtained to show that biliary metabolites of HCBD are reabsorbed and excreted via the kidneys. The glutathione conjugate, its mercapturic acid derivative, and bile containing HCBD metabolites were all nephrotoxic when dosed orally to rats. In common with HCBD, these metabolites caused localized damage to the kidney with minimal effects in the liver. Rats fitted with a biliary cannula were completely protected from kidney damage when dosed with HCBD, demonstrating that hepatic metabolites were solely responsible for the nephrotoxicity of this compound. It is proposed that the hepatic glutathione conjugate of HCBD was degraded to its equivalent cysteine conjugate which was cleaved by the renal cytosolic enzyme beta-lyase to give a toxic thiol which caused localized kidney damage. A urinary sulphenic acid metabolite of HCBD has been identified which is consistent with this hypothesis. The mode of activation of HCBD conjugates in the kidney is believed to be analogous to that proposed for S-(1,2-dichlorovinyl)-L-cysteine.

Animals↗
PubMed1984

Nephrotoxicity of hexachloro-1,3-butadiene in the mouse: the effect of age, sex, strain, monooxygenase modifiers, and the role of glutathione.

Administration of a single ip dose of hexachloro-1,3-butadiene (HCBD) to adult male or female Alderley Park mice at 96 mumol/kg or above produced renal tubular necrosis of the pars convoluta and pars recta of the proximal tubule by 24 hr. Renal damage was also observed biochemically by the reduced accumulation of the organic anion (p-aminohippurate) and organic cation (tetraethylammonium) by renal slices and by an elevated plasma urea. The toxicity of HCBD to adult Alderley Park mice was similar for males and females. Young male mice (21 and 28 days old) were slightly more susceptible to HCBD-induced nephrotoxicity than adult (7-week-old) males. A strain difference in susceptibility to HCBD-induced renal damage was observed, the BALB/c strain being slightly more sensitive than C57BL/10J, C3H, DBA/2J, and Alderley Park strains. This strain difference was reflected in the lethality of HCBD to mice. Prior administration of the monooxygenase inducers, phenobarbitone or beta-naphthoflavone, or of the monooxygenase inhibitor, piperonyl butoxide, did not alter the extent of renal damage produced by HCBD in male Alderley Park mice. However, HCBD produced a marked decrease in kidney but not liver nonprotein sulfydryl content in this strain of mouse, suggesting the formation of glutathione conjugates in the kidney. Administration of the glutathione or N-acetylcysteine conjugates of HCBD produced a marked renal tubular necrosis similar to that seen with HCBD. It is suggested that the mechanism of HCBD-induced nephrotoxicity in the mouse involves nonoxidative metabolism of HCBD in the kidney and that the cysteine conjugates formed are further metabolized to a nephrotoxic agent.

Acetylcysteine↗
PubMed1984

Hexachloro-1:3-butadiene-induced renal tubular necrosis in the mouse.

Administration of hexachloro-1:3-butadiene (HCBD) intraperitoneally at a dose of 50 mg/kg body weight caused necrosis of the proximal tubule of the mouse kidney. The earliest morphological changes detectable by light microscopy were observed after 4 h, and by 16 extensive proximal tubular necrosis was seen throughout the cortex. Active tubular regeneration was apparent by day 5 and by day 14 substantial recovery of morphology had occurred. In the electron microscope mitochondrial swelling was seen 1 and 2 h after dosing in the S1 and S2 segments of the proximal tubule, whereas by 4 and 8 h the major pathological changes were confined to the lower S2 and S3 segments and consisted of mitochondrial swelling and cellular necrosis. The extent of renal injury and regeneration correlated well with measurement of renal function. In conclusion, HCBD produces necrosis of the S2 and S3 segments of the proximal tubule in the mouse, this pattern of injury is different from that seen in the rat where HCBD produces selective necrosis of the S3 segment.

Acute Kidney Injury↗
PubMed1984

The pathogenesis and effect on renal function of nephrocalcinosis induced by different diets in female rats.

The ability of three diets to produce nephrocalcinosis in female rats has been compared after 30, 60 and 90 days of feeding. Severe nephrocalcinosis with associated tubular damage was induced with a standard laboratory maintenance low-protein diet and with a diet containing a single-cell protein (Pruteen) but not with a casein-containing diet. Both the Pruteen and casein diets were high-protein diets. The development of the lesion was equally rapid following feeding of either the laboratory maintenance diet or the Pruteen diet. Nephrocalcinosis was present, with body kidneys similarly affected, at each 30-day interval with either diet. A severe degree of nephrocalcinosis was associated with widespread renal damage although signs of tubular regeneration and repair were evident at 30 days. Nephrocalcinosis induced by the Pruteen diet was accompanied by enlargement of the kidney. Renal function was assessed at each time by the measurement of urine volume, specific gravity and protein content, inulin clearance, and the excretion of the urinary enzymes N-acetyl-beta-glucosaminidase and alkaline phosphatase. Despite extensive calcification and some tubular damage, renal function was unimpaired, reflecting the capacity of the functional reserve of the kidney.

Animals↗
PubMed1984

Role of microsomal and cytosolic glutathione S-transferases in the conjugation of hexachloro-1:3-butadiene and its possible relevance to toxicity.

The mechanism of hexachloro-1:3-butadiene (HCBD)-induced glutathione depletion in male and female rats has been investigated in rat liver and kidney preparations in vitro in order to characterize the enzymes involved and to study the relationship between this effect and the nephrotoxic action of this compound. HCBD caused a marked reduction in glutathione concentration when incubated with male or female hepatic microsomal or cytosolic fractions fortified with glutathione. In contrast with that reported for other halo-olefin's, the depletion of glutathione in the microsomal fraction is not related to the formation of metabolites via cytochrome P-450. The microsomal rate of depletion appeared to be due to a direct reaction catalyzed by a microsomal glutathione S-transferase. A glutathione adduct of HCBD was isolated by thin-layer chromatography and mass spectral analysis strongly indicates the structure to be as S-(1,1,2,3,4-pentachloro-1,3-butadienyl)glutathione, confirming a direct substitution reaction without prior oxidation. This conjugate was formed at a faster rate by the hepatic microsomal fraction than by the cytosolic fraction suggesting a major role for the microsomal glutathione S-transferases in the disposition of this compound. A second more polar glutathione-dependent adduct which may be a double conjugate was formed with cytosol. Glutathione adducts were also formed by male and female kidney cytosol and microsomal fractions but at a slower rate than in liver fractions. It is suggested that the glutathione conjugate of HCBD may be converted to the cysteine derivative, the structure of which is similar to that of S-dichloro-vinyl-L-cysteine and therefore may be nephrotoxic by a similar mechanism.

Animals↗
PubMed1982

Characterization of the effects of known hepatic monooxygenase inducers on male and female rat and mouse kidneys.

Few studies have been designed to quantify the response of the mammalian kidney to agents known to induce monooxygenase activity of renal monooxygenase response to three agents representing different classes of inducers: 2,4,2',4'-tetrachlorobiphenyl (2,4,2',4',-TCB), representative of the barbiturate class, beta-naphthoflavone (BNF), representative of the polycyclic aromatic hydrocarbon class and isosafrole (ISO) as a novel class of inducing agent. Studies were carried out using adult rats and mice of both sexes. Treatment with BNF and ISO stimulated ethoxycoumarin and ethoxyresorufin deethylase activities in renal microsomes from male and female rats and mice, whereas treatment with 2,4,2',4',-TCB had no effect on either enzyme in rats of either sex. NADPH-cytochrome-c-reductase activity was unaffected by any treatment. In rat renal microsomes, cytochromes P-450 and b5 were increased by treatment with BNF and ISO but were not altered by 2,4,2',4'-TCB. Sodium dodecyl sulphate-polyacrylamide gel treated with BNF showed the appearance of a protein band in the 50-60000 dalton range which is similar to that observed in liver microsomes following BNF treatment. These studies confirm and extend previous observations that rat kidney is refractory to induction by inducers of the phenobarbital class, but responds to ISO and the polycyclic aromatic class of inducers. In addition, the studies have demonstrated the presence of a protein in renal microsomes after pretreatment of rats with BNF that was not apparent in microsomes from control rat kidneys.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1982

Hydropic change in rat liver induced by hexachloro-1:3-butadiene.

The effect of a single i.p. dose of 200 or 300 mg kg-1 hexachloro-1:3-butadiene (HCBD) on liver morphology, water, sodium and potassium ion content, cation movement and non-protein sulphydryl (NP-SH) content has been studied in rats. There was a rapid, dose-related increase in liver water which reached a maximum between 16 and 24 h after HCBD administration and then returned to control values by day 4. Associated with the increased water, there was an increase in the Na+ and K+ ions when related to the dry weight of the liver. However, the actual concentration of both cations in total liver water did not alter. The total liver DNA, protein or cytochrome P-450 concentration did not change, at a time when there was a maximal increase in liver water. There was a rapid decrease in liver NP-SH, which reached a nadir (50% of control) 8 h after HCBD administration, then increased to 150% of normal on day 5 and returned to normal by day 10. On histopathological examination, the liver appeared essentially normal, apart from a slight fatty change. Ultrastructural changes were, however, observed 8 h after dosing, when periportal hepatocytes contained occasional swollen mitochondria, whereas centrilobular hepatocytes appeared normal. By 16-24 h, mitochondrial swelling was marked in most periportal hepatocytes and some alteration in smooth endoplasmic reticulum was seen. It is suggested that HCBD or a metabolite causes disruption of mitochondria and this results in an influx of water into the cells. Normal concentrations of Na+ and K+ are, however, maintained by an intact Na+ pump.

Animals↗
PubMed1982

Necrosis of the pars recta (S3 segment) of the rat kidney produced by hexachloro 1:3 butadiene.

Administration of hexachloro 1:3 butadiene (HCBD) intraperitoneally at a dose of 200 mg/kg body weight caused necrosis of the parts recta of the proximal tubules situated in the outer stripe of the outer medulla of the rat kidney. The earliest morphological changes detectable by light microscopy were observed after eight hours, with several proximal tubules showing necrosis. By sixteen hours a distinct band of tubular necrosis was seen in the outer stripe of the outer medulla. One and two days after dosing proximal tubular necrosis was still evident whereas distal tubules were unaffected. By three days, vacuolation was observed in the pars convoluta of some proximal tubules. Active tubular regeneration was apparent by day five, which was accompanied by a marked increase in renal water and nonprotein sulphydryl content (NP-SH). By day fourteen substantial recovery had occurred. Ultrastructural changes were seen as early as one hour after HCBD (300 mg/kg, ip) although necrosis was not marked until 8 hr. Mitochondrial swelling was seen 1-4 hr after dosing in the S1 and S2 segments of the proximal tubule. By 8 hr the major pathological changes were largely confined to the S2 segment and consisted of loss of brush border, mitochondrial swelling and cellular necrosis. In conclusion HCBD produces a site-specific nephrotoxic effect on the proximal tubule in the rat. The pattern of injury was similar to that associated with some other nephrotoxic and ischaemic models of acute renal failure.

Acute Kidney Injury↗