Biochemical mechanisms of cephaloridine nephrotoxicity.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
J B Hook
Publications and source records attributed to J B Hook.
Role of intrarenal biotransformation in chloroform-induced nephrotoxicity in rats.
Various ketonic agents potentiate the hepatic and renal toxicity of halogenated solvents in mice and rats. Characteristics of CHCl3 nephrotoxicity and of 2-hexanone potentiation were evaluated in adult male Fischer 344 rats pretreated with vehicle (oil, 10 ml/kg, po) or 2-hexanone (10 mmol/kg, po) 18 hr prior to CHCl3 exposure. In contrast to the liver, little metabolism of 14CHCl3 by renal cortical microsomes from vehicle- or 2-hexanone-pretreated rats was detected. However, CHCl3 produced a concentration-related dysfunction when added to renal cortical slices from Fischer 344 or Sprague-Dawley rats. The degree of CHCl3 toxicity in vitro was not altered when renal cortical slices were preincubated with CHCl3 (8.5 microliter) under an atmosphere of carbon monoxide. In renal cortical slices, deuterated-CHCl3 was less toxic than CHCl3. Although 2-hexanone pretreatment increased renal slice metabolism of 14CHCl3 twofold, this increase was not associated with an increase in nephrotoxicity after direct exposure of slices to CHCl3 (0 to 10 microliter) in vitro. CHCl3 (0.5 ml/kg, ip) did not alter renal cortical glutathione concentrations in vehicle or 2-hexanone pretreated rats. The association of 14CHCl3-derived radiolabel was increased over control by 2-hexanone pretreatment in protein, lipid, and acid soluble fractions from the renal cortex by approximately two-, two-, and fivefold, respectively. In conclusion, renal cytochrome P-450 did not appear to mediate CHCl3 metabolism and nephrotoxicity in the rat to the extent observed previously in mice. 2-Hexanone appeared to potentiate nephrotoxicity by a mechanism different than that observed in rat liver.
Animals↗
Acetaminophen nephrotoxicity in the rat: quantitation of renal metabolic activation in vivo.
Renal cortical necrosis induced by acetaminophen (APAP) may be related to generation of reactive intermediates by two mechanisms of metabolic activation, direct P-450 dependent metabolic activation (P-450) or metabolic activation subsequent to deacetylation of APAP to p-aminophenol (PAP). Generation of arylating intermediates by both pathways of metabolic activation was quantified in cyclohexamide (HEX)-pretreated or naive rats in vivo with specifically labeled [14C]APAP. The association of each type of metabolic activation with APAP-induced nephrotoxicity was determined in Fischer 344 (F344) and Sprague-Dawley (SD) rats, strains that are susceptible and resistant to APAP-induced nephrotoxicity, respectively. Covalent binding of [ring-14C]APAP to renal cortex was approximately four times greater than [acetyl-14C]APAP in HEX-pretreated F344 rats. In contrast, in SD rats pretreated with HEX covalent binding of [ring-14C]APAP and [acetyl-14C]APAP in the renal cortex was not different. Furthermore, covalent binding of [ring-14C]APAP to renal cortical protein was approximately four times greater in F344 rats than in SD rats. Arylation of hepatic protein by either [ring-14C]APAP or [acetyl-14C]APAP was similar regardless of strain or pretreatment regimen. These studies demonstrated arylation of renal macromolecules in vivo by reactive intermediates resulting from PAP in F344 but not SD rats. Since F344, but not SD, rats are susceptible to APAP-induced nephrotoxicity, it appears the formation of arylating intermediates by PAP is a requisite step in APAP-induced nephrotoxicity.
Acetaminophen↗
The role of p-aminophenol in acetaminophen-induced nephrotoxicity: effect of bis(p-nitrophenyl) phosphate on acetaminophen and p-aminophenol nephrotoxicity and metabolism in Fischer 344 rats.
Acetaminophen (APAP) produces proximal tubular necrosis in Fischer 344 (F344) rats. Recently, p-aminophenol (PAP), a known potent nephrotoxicant, was identified as a metabolite of APAP in F344 rats. The purpose of this study was to determine if PAP formation is a requisite step in APAP-induced nephrotoxicity. Therefore, the effect of bis(p-nitrophenyl) phosphate (BNPP), an acylamidase inhibitor, on APAP and PAP nephrotoxicity and metabolism was determined. BNPP (1 to 8 mM) reduced APAP deacetylation and covalent binding in F344 renal cortical homogenates in a concentration-dependent manner. Pretreatment of animals with BNPP prior to APAP or PAP administration resulted in marked reduction of APAP (900 mg/kg) nephrotoxicity but not PAP nephrotoxicity. This result was not due to altered disposition of either APAP or acetylated metabolites in plasma or renal cortical and hepatic tissue. Rather, BNPP pretreatment reduced the fraction of APAP excreted as PAP by 64 and 75% after APAP doses of 750 and 900 mg/kg. BNPP did not alter the excretion of APAP or any of its non-deacetylated metabolites nor did BNPP alter excretion of PAP or its metabolites after PAP doses of 150 and 300 mg/kg. Therefore, the BNPP-induced reduction in APAP-induced nephrotoxicity appears to be due to inhibition of APAP deacetylation. It is concluded that PAP formation, in vivo, accounts, at least in part, for APAP-induced renal tubular necrosis.
Acetaminophen↗
Cephaloridine nephrotoxicity: strain and sex differences in mice.
Marked species and sex differences have been observed in the nephrotoxicity to the cephalosporin antibiotic cephaloridine (CPH). Preliminary studies have also indicated significant strain differences in mice to CPH nephrotoxicity. To investigate these findings further, male and female C57BL, BALB/c, CD-1, CFW, CBA/J, and DBA/2 mice were given either 4000 or 6000 mg/kg of CPH, sc. Renal function was assessed 48 hr later by the ability of renal cortical slices to accumulate the organic ions p-aminohippurate (PAH) and tetraethylammonium (TEA), changes in blood urea nitrogen (BUN) and kidney-to-body wt ratios. CPH produced dose-dependent nephrotoxicity in C57BL female mice. After 6000 mg/kg, PAH and TEA slice-to-medium (S/M) ratios were reduced by 70 and 49%, respectively; BUN was elevated 10-fold. The same dose given to CFW females had no effect. BALB/c, CD-1, CBA/J, and DBA/2 females showed intermediate signs of toxicity. Male mice of all strains tested exhibited no nephrotoxicity. CPH nephrotoxicity has been correlated with the concentration of CPH within the tubular cell; and C57BL female mice had relatively greater intracellular accumulation of CPH than C57BL male mice and CFW female mice in vitro and in vivo. Thus, differences in net renal cortical accumulation of CPH suggest possible differences in transport, binding, and/or metabolism of CPH may exist among strains and between sexes of mice.
Animals↗
Effects of gentamicin on renal function in isolated perfused kidneys from male and female rats.
The isolated perfused rat kidney was used to determine whether sex differences in gentamicin nephrotoxicity are related to intrinsic differences in renal response to gentamicin. Acute exposure to gentamicin decreased fractional reabsorption of water and electrolytes without changes in glomerular filtration rate in both sexes. Gentamicin decreased the tubular reabsorption of lysozyme but not glomerular permeability to lysozyme. No sex differences in renal responses were observed following in vitro exposures to gentamicin, suggesting that sex differences in susceptibility to gentamicin in vivo may be attributable to extrarenal factors, such as pharmacokinetics.
Absorption↗
Biochemical mechanisms of nephrotoxicity.
Explore the source record for details and available documents.
Acetaminophen↗
Characteristics of renal UDP-glucuronyltransferase.
Rat renal microsomes catalyzed the glucuronidation of l-naphthol, 4-methylumbelliferone and p-nitrophenol, whereas morphine and testosterone conjugation were not detected. In contrast, all five substrates were conjugated by hepatic microsomes; the activity was typically 5-10 times greater than with renal microsomes. Renal microsomal UDP-glucuronyltransferase toward l-naphthol was fully activated (six-fold) by 0.03% deoxycholate while the hepatic enzyme was fully activated (eight-fold) by 0.05% deoxycholate. Full activation of hepatic UDP-glucuronyltransferase occurred when microsomes had been preincubated at 0 C with deoxycholate for 20 min. This effect of preincubation was not observed with renal microsomes. The presence of 0.25M sucrose in the buffers during renal microsomal preparation resulted in a two-fold greater rate of l-naphthol conjugation in both unactivated and activated microsomes than renal microsomes prepared in phosphate buffers alone. Preparation of hepatic microsomes with or without 0.25M sucrose had no effect on UDP-glucuronyltransferase activity. Unactivated (-deoxycholate) renal enzyme was activated when incubations were done at a low pH (5.7), whereas fully activated (0.03% deoxycholate) renal microsomal UDP-glucuronyltransferase displayed a pH optimum at 6.5. Renal microsomal UDP-glucuronyltransferase activity toward l-naphthol, p-nitrophenol and 4-methylumbelliferone was induced by pretreatment of rats with beta-naphthoflavone and trans-stilbene oxide but not by phenobarbital or 3-methylcholanthrene. These data demonstrate that renal UDP-glucuronyltransferases are different from the hepatic enzymes with regard to biochemical properties, substrate specificity and in response to chemical inducers of xenobiotic metabolism.
Animals↗
Mechanism of chloroform nephrotoxicity. IV. Phenobarbital potentiation of in vitro chloroform metabolism and toxicity in rabbit kidneys.
Metabolism of chloroform (CHCl3) by a cytochrome P-450-dependent process to a reactive metabolite may be required to elicit hepatic and renal toxicities. Specific inducers or inhibitors of cytochrome P-450 have been employed frequently as tools to demonstrate this relationship between metabolism and toxicity in the liver. The experiments reported herein were designed to identify the relationship between metabolism and toxicity of CHCl3 in the kidney of rabbits, a species in which renal cytochrome P-450 is induced by phenobarbital. Pretreatment with phenobarbital enhanced the toxic response of renal cortical slices to CHCl3 in vitro as indicated by decreased p-aminohippurate and tetraethylammonium accumulation. Phenobarbital pretreatment also potentiated in vitro 14CHCl3 metabolism to 14CO2 and covalently bound radioactivity in rabbit renal cortical slices and microsomes. Addition of L-cysteine significantly reduced covalent binding in renal microsomes from both phenobarbital-treated and control rabbits and was associated with the formation of the radioactive phosgene-cysteine conjugate 2-oxothiazolidine-4-carboxylic acid (OTZ). Formation of OTZ was enhanced in renal microsomes from phenobarbital-pretreated rabbits. Thus, this in vitro model supports the hypothesis that the kidney metabolizes CHCl3 to the nephrotoxic metabolite, phosgene.
Animals↗
Effect of sex hormone status on chloroform nephrotoxicity and renal mixed function oxidases in mice.
In mice, only males are susceptible to chloroform (CHCl3) nephrotoxicity and the susceptibility appears to be related to renal mixed function oxidase activity. There were sex-related differences of renal cytochrome P-450 and b5 concentrations and of ethoxycoumarin O-deethylase activity in mouse kidneys; in all cases activity was higher in males. Castration of male mice eliminated susceptibility to CHCl3 nephrotoxicity and reduced renal mixed function oxidases to concentrations observed in female mice. Treatment of male and female mice with testosterone increased the susceptibility to CHCl3 nephrotoxicity and increased renal mixed function oxidases to similar activities in both sexes. Previous data have suggested that CHCl3 is metabolized in situ by the kidney, possibly by a mechanism similar to that occurring in the liver. The data from this investigation are consistent with the concept that CHCl3 is metabolized by a cytochrome P-450-dependent mechanism in the kidney.
Animals↗
Nephrotoxicity of phenolic bromobenzene metabolites in the mouse.
Bromobenzene, at doses greater than 5.7 mmol/kg, produced renal proximal tubular necrosis and renal functional changes in mice. p-Bromophenol and o-bromophenol were the major urinary phenolic bromobenzene metabolites although m-bromophenol and 4-bromocatechol were also excreted in detectable quantities. With the exception of o-bromophenol, urinary metabolites were excreted primarily as conjugates. 4-Bromocatechol and the 3 bromophenol isomers were nephrotoxicants (measured as increased blood urea nitrogen and decreased accumulation of organic anions by renal cortical slices) but not hepatotoxicants (measured as serum glutamic pyruvate transaminase) in vivo at 0.56 mmol/kg (i.v.). Preincubation of renal cortical slices with each of these bromobenzene metabolites for 90 min resulted in dose-dependent decreases in the accumulation of p-aminohippurate and tetraethylammonium. At 10 mumol/preincubation (2.4 mM), organic ion accumulation was decreased maximally by all bromobenzene metabolites examined while equimolar amounts of bromobenzene were without effect. 4-Bromocatechol was the most potent nephrotoxicant in vitro. Administration of 0.53-2.12 mmol/kg (i.v.) 4-bromocatechol to mice resulted in a dose-dependent decrease in renal function while hepatic function was altered only slightly at the higher doses. The renal cortical necrosis produced by in vivo administration of 4-bromocatechol could not be distinguished histologically from that induced by bromobenzene. These results demonstrate that 4-bromocatechol and the 3 bromophenol isomers are nephrotoxicants that can be generated from bromobenzene in mice.
Animals↗
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↗
Application of fast atom bombardment mass spectrometry to biological samples: analysis of urinary metabolites of acetaminophen.
Fast atom bombardment (FAB) is useful for the characterization of all major metabolites of the analgesic acetaminophen (APAP). It is particularly useful for providing mass spectra of the polar glucuronide and sulfate conjugates which eluded identification by field desorption and other more conventional methods of ionization. A protocol is described for the use of FAB in the identification of urinary APAP metabolites isolated by reversed phase high-performance liquid chromatography (HPLC) following therapeutic dosages of the drug. A tentative set of recommendations for the off-line use of HPLC and FAB is directed towards solving problems encountered when using these two analytical techniques in concert. In addition, a method for calculating the signal to background ratio (S/B) for analyte peaks in FAB spectra from selected relative ion intensities is proposed. Examples are presented that show the potential of S/B as an empirical parameter for judging the quality of FAB spectra.
Acetaminophen↗
Renal processing of low molecular weight proteins.
Previous renal clearance studies provided quantitative data concerning renal reabsorption of proteins while the simultaneous processes of renal accumulation and degradation remain, to a great extent, insufficiently investigated. Thus, it was the aim of this study to measure renal reabsorption of egg-white lysozyme at various lysozyme concentrations and to relate the corresponding accumulation and degradation of lysozyme to the lysozyme transport rates in intact rats and isolated perfused rat kidneys. Lysozyme (with 125I-lysozyme in certain experiments), was continuously infused i.v. or added to the perfusate to achieve plasma (or perfusate) concentrations of lysozyme (PLY) of approximately 50, 500 or 1000 mg X 1(-1) for periods of time varying between 3 and 120 or 150 min. Clearances of inulin and lysozyme or the total content of radioactivity and the trichloroacetic acid (TCA)-soluble radioactivity in the kidney tissue were determined at the end of clearance or accumulation periods. Additionally the perfusate concentration of the metabolite tyrosine was measured by high performance liquid chromatography (HPLC). The reabsorption rates of lysozyme (TLY) were concentration-dependent in both intact rats and isolated perfused rat kidney. After 25 min of lysozyme infusion, the lysozyme reabsorption rates amounted to 37, 245 and 331 micrograms X min-1 X g-1 kidney at the above lysozyme concentrations. After the same infusion time, the accumulation rates of lysozyme were 8, 59 and 118 micrograms X min-1 X g-1 kidney. The difference between the transport rate and accumulation rate should represent the renal degradation rate of lysozyme.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Mechanism of chloroform nephrotoxicity. III. Renal and hepatic microsomal metabolism of chloroform in mice.
In vitro studies with male ICR mouse renal cortical slices have indicated that chloroform (CHCl3) is metabolized by the kidney to a nephrotoxic intermediate, possibly by a cytochrome P-450-dependent mechanism similar to that occurring in the liver. In this investigation, metabolism of 14CHCl3 by microsomes prepared from renal cortex and liver provided definitive evidence for a role of cytochrome P-450 in the renal metabolism and toxicity of CHCl3. 14CHCl3 was metabolized to 14CO2 and covalently bound radioactivity by male renal cortical microsomes; metabolism required oxygen, a NADPH regenerating system, was dependent on incubation time, microsomal protein concentration, and substrate concentration, and was inhibited by carbon monoxide. Consistent with the absence of CHCl3 nephrotoxicity in female mice, little or no metabolism of 14CHCl3 by female renal cortical microsomes was detected. CHCl3 produced a type I binding spectrum with oxidized male renal cortical and hepatic microsomes. Incubation of glutathione with microsomes and 14CHCl3 increased the amount of aqueous soluble metabolites detected with a concomitant decrease of metabolism to 14CO2 and covalently bound radioactivity, suggesting the formation of a phosgene conjugate as has been described for hepatic CHCl3 metabolism. These data support the hypothesis that renal cytochrome P-450 metabolizes CHCl3 to a nephrotoxic intermediate.
Animals↗
Nephrotoxicity of chloroform: metabolism to phosgene by the mouse kidney.
In this investigation, we have attempted to determine whether chloroform (CHCl3)-induced nephrotoxicity might be due to its metabolism to phosgene (COCl2) in the kidney. We have found that kidney homogenates from DBA/2J male mice in the presence of glutathione metabolize CHCl3 to 2-oxothiazolidine-4-carboxylic acid (OTZ). This product appears to be formed by the initial trapping of COCl2 by two molecules of GSH to form diglutathionyl dithiocarbonate (GSCOSG). Kidney gamma-glutamyl transpeptidase can rapidly metabolize GSCOSG to N-(2-oxothiazolidine-4-carbonyl)-glycine which is then hydrolyzed, possibly by cysteinyl glycinase to OTZ. The finding that deuterium-labeled chloroform (CDCl3) was less nephrotoxic and depleted less renal GSH than did CHCl3 suggests that the metabolism of CHCl3 to COCl2 may also occur in the kidney in vivo and lead to nephrotoxicity.
Animals↗
Effect of polybrominated biphenyls, beta-naphthoflavone and phenobarbital on arylhydrocarbon hydroxylase activities and chloroform-induced nephrotoxicity and hepatotoxicity in male C57BL/6J and DBA/2J mice.
Administration of chloroform (CHCl3) to male C57/6J (C57) and DBA/2J (DBA) mice produced dose-dependent hepatic and renal damage. Hepatic arylhydrocarbon hydroxylase (AHH) activity was higher in C57 than DBA mice; in kidney, AHH activity was higher in DBA than in C57 mice. CHCl3 caused the same degree of liver damage in both strains of mice; however, nephrotoxicity of CHCl3 was greater in DBA than in C57 mice. Pretreatment of C57 and DBA mice with phenobarbital (PB) markedly increased hepatic AHH activity and hepatotoxicity of CHCl3 in both strains but did not affect renal AHH or nephrotoxicity of CHCl3. Similarly, beta-naphthoflavone (BNF) enhanced AHH activity and CHCl3 hepatotoxicity in C57 mice, but had little effect on nephrotoxicity. BNF did not affect hepatic AHH nor CHCl3-induced hepatic injury in male DBA mice. Pretreatment with polybrominated biphenyl (PBB) enhanced AHH activity in liver and CHCl3 hepatotoxicity in both strains. After PBB, nephrotoxicity of CHCl3 and renal AHH activity were increased in C57 mice whereas PBB did not alter nephrotoxicity or renal AHH in DBA mice. These results suggest that CHCl3-nephrotoxicity is independent of hepatotoxicity.
Alanine Transaminase↗
Sex and strain differences in mouse kidney: Bowman's capsule morphology and susceptibility to chloroform.
Chloroform (CHCl3) produces liver damage in male and female mice but renal injury only in male mice. Previous reports demonstrated that the parietal epithelium of Bowman's capsule in female mice is composed of squamous cells, whereas the parietal cells of Bowman's capsule from male mice consist of a mixture of squamous and cuboidal cells or purely cuboidal cells. These data suggested that the factor(s) associated with these histological differences may similarly be associated with factors that determine susceptibility to tubular damage from chloroform. The susceptibility of male mice to chloroform nephrotoxicity varies with animal strain. In the present study, administration of CHCl3 to male C57BL/6J (C57) and male and female DBA/2J (DBA) mice produced dose-dependent kidney tubular damage in male C57 and male DBA mice. However, CHCl3 nephrotoxicity was considerably greater in male DBA mice than in male C57 mice. Female DBA mice failed to develop renal damage following administration of CHCl3. Male DBA mice had a higher percentage of cuboidal parietal epithelial cells in Bowman's capsule whereas male C57 mice had a higher percentage of squamous cells in the parietal epithelium. The parietal epithelium in Bowman's capsule of female DBA mice was predominantly squamous. Since morphological differences between sex and strain of mice occurred in the capsular epithelium, and the differences in susceptibility to CHCl3 appear to be a tubular phenomenon, it is unlikely that there is a causal relationship between the structure of Bowman's capsule and chloroform-induced renal tubular necrosis; rather, these two independent phenomena are regulated by some common factor(s), possibly testosterone.
Alanine Transaminase↗