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E A Lock

Publications and source records attributed to E A Lock.

At least 91 records · Page 5Linked to original sources
PubMed1989

Pentachlorobutadienyl-L-cysteine uncouples oxidative phosphorylation by dissipating the proton gradient.

A very early event in the toxicity of pentachlorobutadienyl-L-cysteine (PCBC) to rabbit renal proximal tubules is uncoupling of oxidative phosphorylation (R.G. Schnellmann, E. A. Lock, and L. J. Mandel (1986), Toxicologist 6, 176; (1987), Toxicol. Appl. Pharmacol. 90, 521). The mechanism of PCBC uncoupling of mitochondrial oxidative phosphorylation has been investigated using isolated rabbit renal cortical mitochondria (RCM). PCBC increased state 4 respiration of RCM respiring on pyruvate/malate or succinate in a concentration (10-100 microM)- and time (1-5 min)-dependent manner. PCBC also increased state 4 respiration in the presence of oligomycin, an inhibitor of F0F1-ATPase. The effect of PCBC on mitochondrial proton permeability was determined by measuring passive mitochondrial swelling. After a 2-min exposure to PCBC, RCM swelled when placed in NH4Cl or NaCl, but not KCl or sucrose. The protonophore carbonyl cyanide p-trifluoromethoxyphenyl hydrazone (FCCP) (1 microM) produced similar effects. After 5 min, RCM swelled when placed in NH4Cl, NaCl, or KCl, but not in sucrose. Aminooxyacetic acid, an inhibitor of cysteine conjugate beta-lyase, blocked the effects of PCBC on respiration, indicating that PCBC can be metabolized by RCM to produce RCM toxicity. These results show that PCBC initially uncouples oxidative phosphorylation by dissipating the proton gradient. Subsequently, additional ion permeabilities occur. These results are in complete agreement with previous observations in rabbit renal proximal tubule suspensions.

Animals↗
PubMed1989

Involvement of reversible binding to alpha 2u-globulin in 1,4-dichlorobenzene-induced nephrotoxicity.

Similarly to unleaded gasoline, 1,4-dichlorobenzene (1,4-DCB) administered for 2 years caused a dose-related increase in the incidence of renal tumors in male but not in female rats or in either sex of mice. Unleaded gasoline and 2,2,4-trimethylpentane (TMP), a component of unleaded gasoline, increased protein droplet formation and cell proliferation in male but not in female rat kidneys. These protein droplets contained, alpha 2u-globulin, a male rat-specific low-molecular-weight protein and 2,4,4-trimethyl-2-pentanol, a metabolite of TMP that was reversibly bound to this protein. Studies were undertaken to determine if 1,4-DCB produced similar effects; 1,2-DCB was used for comparison since it did not produce renal carcinogenesis in male rats. Gel filtration chromatography of a 116,000g supernatant prepared from kidneys of 1,4-[14C]DCB-treated rats showed that radiolabel coeluted with alpha 2u-globulin as one sharp peak as opposed to a multipeak pattern observed for 1,2-[14C]DCB; the maximal quantity of radiolabel for 1,4-DCB was twice that for 1,2-DCB. Equilibrium dialysis of kidney cytosol in the presence or absence of sodium dodecyl sulfate demonstrated that the radiolabel was reversibly bound to alpha 2u-globulin; the amount for 1,4-[14C]DCB-treated rats was almost twice as much as that for 1,2-[14C]DCB-treated rats. 1,2-DCB was also shown to be covalently bound to renal alpha 2u-globulin, and covalently bound to liver and plasma high-molecular-weight proteins. 1,4-DCB and, to a minor extent, 2,5-dichlorophenol, the major metabolite of 1,4-DCB, were reversibly bound to renal alpha 2u-globulin from 1,4-DCB-treated rats. 1,4-DCB increased protein droplet formation in male but not in female rat kidneys, whereas equimolar doses of 1,2-DCB showed no effect in either sex. Renal cell proliferation, measured by [3H]thymidine incorporation into renal DNA, was increased after 1,4-DCB but not after 1,2-DCB treatment. Nephrotoxicity and biochemical alterations induced by 1,4-DCB resemble those of unleaded gasoline and suggest that a similar mechanism is involved in the induction of alpha 2u-globulin nephropathy in male rats.

Alpha-Globulins↗
PubMed1989

Cysteine conjugate beta-lyase of rat kidney cytosol: characterization, immunocytochemical localization, and correlation with hexachlorobutadiene nephrotoxicity.

Cysteine conjugate beta-lyase (beta-lyase) was purified to electrophoretic homogeneity from the kidney cytosol of male Wistar rats. The highly purified enzyme exhibited a monomeric molecular weight of 50,000 Da and was active in the alpha-beta elimination of cysteine conjugates including S-(1,2-dichlorovinyl)-L-cysteine (DCVC), S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC), and S-(2-benzothiazolyl)-L-cysteine, particularly toward DCVC and TFEC. The purified enzyme also exhibited glutamine transaminase K activity with phenylalanine and alpha-keto-gamma-methiolbutyrate as substrates. An antibody was raised to the purified rat protein in sheep and the crude immune serum affinity purified, yielding a specific antibody that recognized only the beta-lyase protein in whole kidney homogenates. Immunocytochemical studies on rat kidney sections stained with the purified antibody revealed that the cytosolic beta-lyase enzyme was mainly localized in the pars recta of the proximal tubule in untreated rats. This localization is coincident with the site-specific kidney necrosis produced by hexachloro-1,3-butadiene (HCBD). These results indicate that the tissue localization of beta-lyase in the proximal tubule plays an important role in determining the specific nephrotoxicity produced by halogenated alkenes such as HCBD.

Animals↗
PubMed1989

Mechanism of nephrotoxic action due to organohalogenated compounds.

A number of organohalogenated chemicals cause nephrotoxicity in experimental animals and man. Studies in animals have shown that metabolic activation of the chemical is required to produce toxicity. Currently, two major pathways of metabolism, mediated either via cytochrome P-450 or glutathione conjugation, have been implicated. Chloroform is discussed as an example of cytochrome P-450-mediated activation and dihaloethanes and hexachloro-1,3-butadiene as examples of glutathione conjugation followed by activation. Acute human exposure to certain organohalogenated compounds can sometimes result in proximal tubular injury. These intoxications usually occur after either accidental or deliberate ingestion and are rarely occupational. Chronic low-level exposure can occur in the work place, and several biological tests have been developed to detect chronic nephrotoxicity. A few studies have been undertaken of workers exposed to organohalogenated chemicals; these have provided no indication that exposure to these chemicals causes chronic renal damage.

Acute Kidney Injury↗
PubMed1988

Olfactory cytochrome P-450. Studies with suicide substrates of the haemoprotein.

1. The olfactory epithelium of male hamsters has been found to be extremely active in the cumene hydroperoxide-supported oxidation of tetramethylphenylenediamine, and this peroxidase activity has been shown to be cytochrome P-450-dependent. 2. The interaction of a series of suicide substrates of cytochrome P-450 with the hepatic and olfactory mono-oxygenase systems has been assessed by determination of peroxidase, 7-ethoxycoumarin O-de-ethylase (ECOD) and 7-ethoxyresorufin O-de-ethylase (EROD) activities after treatment in vivo with these compounds. Chloramphenicol, OOS-trimethylphosphorothiolate and two dihydropyridines [DDC (3,5-diethoxycarbonyl-1,4-dihydrocollidine) and 4-ethyl DDC (3,5-diethoxycarbonyl-4-ethyl-1,4-dihydro-2,6-dimethylpyridine)] all caused similar percentage inhibitions of hepatic and olfactory activities, but the absolute amounts of enzymic activity lost were considerably greater in the latter tissue. In contrast, halothane had little effect upon hepatic cytochrome P-450-dependent reactions, whereas it severely inhibited those of the olfactory epithelium. 3. The time course of loss and recovery of hepatic and olfactory peroxidase, ECOD and EROD activities after a single dose of 4-ethyl DDC was studied. The rates of loss of activity observed were very similar, irrespective of tissue or reaction examined. In the olfactory epithelium, all three activities recovered concurrently and at a rate similar to that of the hepatic peroxidase activity. In contrast, the hepatic de-ethylation of 7-ethoxycoumarin and 7-ethoxy-resorufin recovered significantly more rapidly. 4. It is suggested that this behaviour is due to 4-ethyl DDC acting not only as a suicidal inhibitor but also as an inducer of certain forms of cytochrome P-450 in the liver; in the olfactory epithelium, however, inactivation, but not induction, occurs. Classical inducing agents were reported to have no effect upon olfactory cytochrome P-450, and in the present study neither phenobarbitone nor beta-naphthoflavone treatment had any effect upon olfactory cytochrome P-450-dependent reactions, although it induced those of the liver.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1988

Deacetylation and further metabolism of the mercapturic acid of hexachloro-1,3-butadiene by rat kidney cytosol in vitro.

Hexachloro-1,3-butadiene (HCBD) is more nephrotoxic to female than male rats. Metabolism of HCBD involves conjugation with glutathione followed by formation of the cysteine conjugate S-(pentachloro-1,3-butadienyl) cysteine (PCBD-CYS) and then the mercapturic acid N-acetyl-S-pentachloro-1,3-butadienyl-cysteine (PCBD-NAC). PCBD-NAC is also more nephrotoxic to female rats than male rats. The deacetylation of [14C]-PCBD-NAC to PCBD-CYS and the binding of radiolabelled metabolites to protein has been studied using renal cytosol preparations from male and female rats in vitro, since a sex-related difference in these reactions could explain the difference in nephrotoxicity found in vivo. PCBD-NAC was rapidly metabolised by renal cytosol. The rate of metabolism was similar with either male or female renal cytosol, and the major metabolite identified was PCBD-CYS. N-Acetylation of PCBD-CYS to PCBD-NAC was not detected in the presence of either male or female renal cytosol. Covalent binding of radioactivity from [14C]-PCBD-NAC to cytosolic protein could be detected after 5 min incubation, and although the extent of binding was similar for both male and female cytosol at early time periods, after 60 min incubation more binding was found in the presence of male cytosol. Covalent binding was largely prevented by aminooxyacetic acid, an inhibitor of cysteine conjugate beta-lyase, suggesting a role for this enzyme in the activation of HCBD. These results indicate that the sex differences in the nephrotoxicity of HCBD and PCBD-NAC in the rat are not attributable to differences in the rate of deacetylation of PCBD-NAC to give the proximate nephrotoxin PCBD-CYS.

Acetylation↗
PubMed1988

Studies on the mechanism of nephrotoxicity and nephrocarcinogenicity of halogenated alkenes.

There is now a considerable weight of evidence from studies in a number of different laboratories with different haloalkenes to suggest that these compounds undergo conjugation with glutathione followed by degradation of the S-conjugate (Figure 1) to produce cytotoxic, and in some cases mutagenic, metabolites. These effects are dependent upon the sequential metabolism by gamma-glutamyl transferase and dipeptidases to produce the cysteine conjugates, and the presence of renal transport systems which concentrate the chemical in renal cells. These conjugates then appear to undergo further metabolism to a reactive thiol by the renal enzyme cysteine-conjugate beta-lyase, a process which can be blocked by inhibiting the enzyme with AOAA. Renal beta-lyase is present in both the cytosol and mitochondrial fractions, but toxicity studies in isolated cells and mitochondria indicate that the primary mode of action of these compounds is the inhibition of mitochondrial respiration, suggesting that the mitochondrial beta-lyase may be more important than the cytosolic enzyme in cysteine S-conjugate bioactivation. In addition to the renal cell injury caused by the presumed reactive thiol metabolite, reaction with DNA also occurs as the chlorinated, but not fluorinated, analogs are mutagenic, and in the case of HCBD, carcinogenic. Thus the target organ, cellular and subcellular specificity of haloalkene-S-conjugates, is due to the presence of bioactivating enzymes and the susceptibility of certain biochemical processes. The precise relationship between (1) the mitochondrial effects and cytotoxicity and (2) the interaction of the chemical with DNA and its mutagenicity require more precise understanding in order to elucidate the mechanism of S-conjugate-induced cell death and carcinogenicity. The routes and rates of metabolism of some of these compounds, with respect to glutathione conjugation vs. oxidative metabolism, in both experimental animals and man are required to help assess the risk associated with this class of chemicals.

Alkenes↗
PubMed1987

A mechanism of S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine toxicity to rabbit renal proximal tubules.

S-(1,2,3,4,4-Pentachloro-1,3-butadienyl)-L-cysteine (PCBC) has been identified as the penultimate compound responsible for hexachlorobutadiene-induced nephrotoxicity. The primary goal of these studies was to determine the mechanism of PCBC-induced toxicity in rabbit renal proximal tubules by examining the early changes in tubular physiology. PCBC (20-500 microM) induced a specific sequence of toxic events. Following 15 min of exposure, 200 microM PCBC increased basal (25%) and ouabain-insensitive (78%) respiration. This was followed by a decrease in basal (46%), nystatin-stimulated (54%), and ouabain-insensitive (21%) respiration and a decrease in glutathione content (79%). Finally, there was a decrease in cell viability as measured by a decrease in LDH retention at 60 min. Direct probing of mitochondrial function revealed that the initial increase in respiration resulted from the uncoupling of oxidative phosphorylation, while the late changes in respiration appeared to result from gross mitochondrial damage characterized by inhibited state 3 respiration, inhibited cytochrome c-cytochrome oxidase, and inhibited electron transport. Studies utilizing tubules with decreased glutathione content revealed that glutathione plays little if any role in the early events of PCBC-induced toxicity. These results suggest that PCBC-induced mitochondrial dysfunction may initiate the renal proximal tubule injury.

Animals↗
PubMed1987

2,2,4-Trimethylpentane-induced nephrotoxicity. I. Metabolic disposition of TMP in male and female Fischer 344 rats.

2,2,4-Trimethylpentane (TMP), a component of unleaded gasoline, causes nephrotoxicity in male, but not in female, rats. In the present study, male and female Fischer 344 rats were treated with a single oral dose of [14C]TMP (4.4 mmol/kg; 2 microCi/mmol). Radiolabeled material in kidney, liver, and plasma was determined at 4, 8, 12, 24, and 48 hr after dosing. Maximum concentration of TMP-derived radioactivity in kidney, liver, and plasma of male rats was found after 12 hr (1252, 1000, and 403 nmol eq/g, respectively), whereas those measured in females were found after 8 hr (577, 1163, and 317 nmol eq/g, respectively). A selective retention of the TMP-derived radiolabel in the kidneys of male rats was noted when peak tissue concentration was expressed as a percentage of administered dose. Kidney concentrations of TMP-derived radiolabel increased in a nonlinear, but dose-dependent, manner; the kidney to plasma ratio was greater at low doses than at higher doses. Increased retention of radiolabel material in the kidney was associated with a significant increase in renal concentration of the male-rat-specific protein, alpha 2u-globulin, 24 and 48 hr after TMP administration. Total radioactivity collected in urine 48 hr after TMP administration was similar in males and females (32 and 31% of dose). Identification and quantitation of the urinary metabolites of TMP showed that both male and female rats metabolize TMP via the same pathway and at a similar rate. Female rats, however, excreted more conjugates of 2,4,4-trimethyl-2-pentanol in urine than males. 2,4,4-Trimethyl-2-pentanol was the major metabolite present in the male rat kidney, but was absent in the female rat kidney. The renal retention of 2,4,4-trimethyl-2-pentanol appears to account for the delayed clearance observed in the disposition of [14C]TMP-derived radiolabel. Based on the concomitant accumulations in renal alpha 2u-globulin concentration and renal 2,4,4-trimethyl-2-pentanol concentration, an association is speculated between these two components. The male-rat-specific accumulation of 2,4,4-trimethyl-2-pentanol may therefore reflect the accumulation of a "metabolite-alpha 2u-globulin" complex. This may be relevant to the male-rat-specific nephrotoxicity produced by TMP.

Alpha-Globulins↗
PubMed1987

2,2,4-Trimethylpentane-induced nephrotoxicity. II. The reversible binding of a TMP metabolite to a renal protein fraction containing alpha 2u-globulin.

Trimethylpentane (TMP) produces nephrotoxicity in male but not in female rats. The toxicity is characterized by an increase in protein droplets in proximal convoluted tubular cells and an increase in the renal concentration of the male-rat-specific protein alpha 2u-globulin. Subcellular fractionation of the kidneys from male rats 24 hr after [3H]TMP administration showed that about 60% of the radiolabeled material was localized in the 116,000g supernatant. Column chromatography of this supernatant resolved the radioactivity into two components; one, which contained about 26% of the radiolabel, coeluted with alpha 2u-globulin and cross-reacted with an antibody specific for alpha 2u-globulin. The remaining component eluted in the low-molecular-weight range (less than 1000 Da) and was assumed to be TMP metabolites. Radiolabel from [3H]TMP in male rat urine also resolved into two components with about 0.1% of the radiolabel in urine coeluting with the alpha 2u-globulin-containing fraction. Radiolabel from TMP in male rat liver 116,000g supernatant and plasma and in female rat kidney 116,000g supernatant eluted as a single component in the low-molecular-weight range. Dialysis (1000-Da cutoff) of male kidney 116,000g supernatant led to a loss of the low-molecular-weight components, but nondialyzable radiolabel (about 20%) still coeluted with the alpha 2u-globulin after gel chromatography. Dialysis against 0.1% sodium dodecyl sulfate led to a loss of both the low- and high-molecular-weight radioactive material. These results suggested that the high-molecular-weight radioactive material was formed by the reversible binding of a radioactive component of TMP to a male-rat-specific protein. Gas chromatography-mass spectrometry of an ethyl acetate extract of the alpha 2u-globulin-containing fractions of TMP-treated male rat kidney 116,000g supernatant identified 2,4,4-trimethyl-2-pentanol as the only bound metabolite to alpha 2u-globulin. These studies provide the first evidence for a reversible binding between a metabolite of TMP and a male-rat-specific protein in the kidney and thus provide important insight delineating a potential mechanism of hydrocarbon-induced hyaline-droplet nephropathy.

Alpha-Globulins↗
PubMed1987

The induction of omega and beta-oxidation of fatty acids and effect on alpha 2u globulin content in the liver and kidney of rats administered 2,2,4-trimethylpentane.

The effect of daily administration of 12 mmol/kg 2,2,4-trimethylpentane for 10 d on hepatic and renal microsomal mono-oxygenase activity, peroxisomal beta-oxidation and the concentration of alpha 2u-globulin has been examined in male and female rats. 2,2,4-Trimethylpentane produces liver and, to a lesser extent, kidney enlargement. This is associated with the selective induction of cytochrome P-450-mediated omega-oxidation and peroxisomal beta-oxidation of fatty acids and proliferation of peroxisomes. Male rats show a more marked response than female rats. 2,2,4-Trimethylpentane produces an increase in alpha 2u-globulin in the kidney of male rats. The relevance of selective induction of omega- and beta-oxidation of fatty acids and accumulation of alpha 2u-globulin to renal tubular necrosis in male rats requires further study.

Alpha-Globulins↗
PubMed1986

Immunocytochemical localization of cytochrome P-450 in hepatic and extra-hepatic tissues of the rat with a monoclonal antibody against cytochrome P-450 c.

The cellular distribution of cytochrome P-450 has been studied in the liver and a number of extrahepatic tissues in the rat by immunocytochemistry, using an antibody raised against cytochrome P-450 form c. Immunoreactive cytochrome P-450, most probably form c, was found in the proximal tubules of the kidney, in the Clara cells of the lung, and in the olfactory epithelium and Bowman's glands of the olfactory tissue, in addition to its location in the liver. Immunoreactive cytochrome P-450 was not found in the small intestine, the testes or the adrenal gland, although these organs are known to contain isoenzymes of cytochrome P-450. The use of antibody titration enabled the effects of phenobarbitone, beta-naphthoflavone and clofibrate on the content and distribution of immunoreactive cytochrome P-450 to be studied in both the liver and in the other organs discussed. Phenobarbitone induces epitope-specific cytochrome P-450 in the centrilobular cells of the liver but has no effect in any of the other tissues studied. Clofibrate is without effect on the levels of immunoreactive cytochrome P-450 in any of the tissues studied. In contrast, beta-naphthoflavone induces immunoreactive cytochrome P-450 in the periportal region of the liver, and also in the Clara cells of the lung, in the enterocytes of the small intestine and in the proximal tubules of the kidney. Of all of the tissues studied, in which immunoreactive cytochrome P-450 could be detected, only the olfactory epithelium failed to undergo enzyme induction following treatment with beta-naphthoflavone.

Adrenal Glands↗
PubMed1986

NADPH: cytochrome P-450 reductase in olfactory epithelium. Relevance to cytochrome P-450-dependent reactions.

The presence of a very active cytochrome P-450-dependent drug-metabolizing system in the olfactory epithelium has been confirmed by using 7-ethoxycoumarin, 7-ethoxyresorufin, hexobarbitone and aniline as substrates, and the reasons for the marked activity of the cytochrome P-450 in this tissue have been investigated. The spectral interaction of hexobarbitone and aniline with hepatic and olfactory microsomes has been examined. By this criterion there was no evidence for marked differences in the spin state of the cytochromes of the two tissues, or for the olfactory epithelium containing a greater amount of cytochrome capable of binding hexobarbitone, a very actively metabolized substrate. Rates of NADPH and NADH: cytochrome c reductase activity were found to be higher in the olfactory epithelium than in the liver, and direct evidence was obtained for a greater amount of the NADPH-dependent flavoprotein in the olfactory microsomes. Investigation of male rats and male and female mice, as well as male hamsters, demonstrated that, in all cases, the cytochrome P-450 levels of the olfactory epithelium were lower than those of the liver, while the 7-ethoxycoumarin de-ethylase and NADPH:cytochrome c reductase activities were higher. A correlation was found between 7-ethoxycoumarin de-ethylase and NADPH:cytochrome c reductase activities for both tissues in all species examined. The ratio of reductase to cytochrome P-450 was found to be considerably higher in the olfactory epithelium (1:2-1:3) than in the liver (1:11-1:15), regardless of the species examined, suggesting that facilitated electron flow may contribute significantly to the cytochrome P-450 catalytic turnover in the olfactory tissue.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1986

Alpha 2U-globulin: measurement in rat kidney and relationship to hyaline droplets.

The concentration of renal alpha 2U-globulin increased in a dose-dependent manner in adult male but not female rats which received a single dose of 2,2,4-trimethylpentane (TMP). After administration of a single dose of 12 mmol TMP/kg to adult male rats, the renal concentration of alpha 2U-globulin reached a peak at 48 hours and returned to near background level after 7 days. These changes in renal alpha 2U-globulin concentration were closely paralleled by changes in renal hyaline droplet formation. Renal alpha 2U-globulin and hyaline droplets were absent in normal pre-puberty male rats, and neither could be stimulated by a single dose of TMP. alpha 2U-Globulin was localised in the renal cortex of adult male rats, in particular the S2 segment of the proximal tubule. A greater staining intensity due to alpha 2U-globulin was seen in the S2 and adjacent segments after a single dose of TMP. A strong association is suggested between the presence of renal hyaline droplets and the occurrence of alpha 2U-globulin.

Alpha-Globulins↗
PubMed1986

Inter-relatedness of some isoenzymes of cytochrome P-450 from rat, rabbit and human, determined with monoclonal antibodies.

Monoclonal antibodies have been raised to rat liver cytochromes P-450 b and c, and rabbit liver cytochrome P-450 form 4. A total of six antibodies have been studied. Each antibody reacted strongly both with its homologous antigen and with microsomal fractions selectively enriched with that antigen by treatment of animals with inducing compounds. However, several of the antibodies showed cross-reactivity, either within or between species. A combination of enzyme-linked immunosorbent assay, immunoadsorption, Western blotting and competitive radioimmunoassay revealed that each of the antibodies reacted with a different epitope. Proteolytic digestion of antigen followed by Western blotting of the peptide fragments enabled antibodies, otherwise identical in their reactivity, to be distinguished. It is concluded that complex structural relationships exist amongst the different isoenzymes of cytochrome P-450 and that epitope mapping will help in characterizing both animal and human cytochromes P-450.

Animals↗
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↗
PubMed1986

Induction of renal mixed function oxidases in the rat and mouse: correlation with ultrastructural changes in the proximal tubule.

Rats and mice were pretreated with beta-naphthoflavone (BNF) at 100 mg/kg/day, ip, for 4 days, or polybrominated biphenyl (PBB) as a single ip dose at 150 mg/kg, and the temporal changes in renal mixed function oxidase (MFO) activity and ultrastructural changes in the proximal tubule were examined. Rat renal cytochrome P-450 (P-450), ethoxycoumarin-O-deethylase (ECOD), and ethoxyresorufin-O-deethylase (EROD) were increased 5 days following the first dose of inducer. P-450 content and enzyme activity peaked on Day 5 to Day 10 and returned to control values by Day 15. BNF and PBB caused proliferation of smooth endoplasmic reticulum (SER) in only the S3 segment of the rat proximal tubule. Histologic analysis indicated that there was a close correlation between the temporal changes in renal MFO activity and proliferation of SER in the S3 segment of the proximal tubule. In contrast to the rat, mouse renal P-450 and ECOD were not induced by either BNF or PBB nor was there any significant proliferation of SER in any segment of the proximal tubule. Mouse renal EROD was slightly increased on Day 5 but not Day 10 or 15 by BNF; PBB had no effect. In addition to proliferation of SER, these inducers also caused proliferation of peroxisomes in the rat and mouse proximal tubule. These results demonstrate a temporal relationship between induction of rat renal MFOs and proliferation of SER in specific sections of the proximal tubule and thus suggest that induction of these renal enzymes may also be restricted to specific cell populations of the kidney. A species difference apparently exists since proliferation of SER was not observed in the mouse.

Animals↗