Chao-Hen Kuo

Lipid peroxidation: A possible mechanism of cephaloridine-induced nephrotoxicity

Cephaloridine produces renal cortical injury, but the precise mechanism responsible for this nephrotoxicity remains unclear. Recently cephaloridine has been shown to deplete reduced glutathione (GSH) concentration selectively in renal cortex. Cephaloridine nephrotoxicity can be potentiated by diethyl maleate (a GSH depletor), but no glutathione conjugate can be detected. Thus, it was of interest to investigate further the mechanism of depletion of renal cortical GSH by cephaloridine. In the present study, cephaloridine markedly decreased GSH in rat and rabbit renal cortex while concomitantly increasing oxidized glutathione (GSSG). Furthermore, cephaloridine increased lipid peroxidation specifically in renal cortical cells. Conjugated diene formation (an index of lipid peroxidation) was increased in renal cortex but not in the liver shortly following administration of cephaloridine. Removal of selenium and/or vitamin E from the diet, which should enhance lipid peroxidation, potentiated cephaloridine nephrotoxicity and enhanced cephaloridine-induced morphological damage in the kidney. These findings are consistent with a major role of lipid peroxidation in the etiology of cephaloridine nephrotoxicity.

Depletion of renal glutathione content and nephrotoxicity of cephaloridine in rabbits, rats, and mice

Abstract Cephaloridine produces necrosis of renal proximal tubular cells in humans and experimental animals. The mechanism responsible for this nephrotoxicity still remains unclear. In the present study, cephaloridine toxicity and concomitant changes in tissue glutathione content were determined in rabbits, rats, and mice. Kidney toxicity was evaluated as alterations in kidney-to-body weight ratio, blood urea nitrogen, and kidney slice accumulation of p -aminohippurate and tetraethylammonium. The results demonstrate that cephaloridine is most nephrotoxic to rabbits, intermediate in toxicity to rats, and least toxic to mice, confirming previous histopathological findings. Furthermore, cephaloridine produced a dose-related depletion of glutathione in the renal cortex but not in the medulla shortly after the injection. The relative susceptibility of these three species to glutathione depletion paralleled species differences in nephrotoxicity of cephaloridine. In addition, pretreatment of animals with diethyl maleate potentiated cephaloridine nephrotoxicity, strongly suggesting a relationship between glutathione depletion and cephaloridine toxicity.

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.

Effect of monocrotaline ingestion on liver, kidney, and lung of rats

Abstract Young, male rats were administered monocrotaline (MCT) ad libitum in the drinking water (22 μg/ml) for up to 28 days, and the development of toxicity in lung, liver, and kidney was examined. Clearance of perfused 5-hydroxytrytptamine by isolated lungs of treated rats was decreased as early as 14 days. This was accompanied by increases in lung/body weight ratio and in lactate dehydrogenase activity in cell-free bronchopulmonary lavage fluid. Hypertrophy of the right heart and increased inflow perfusion pressure of isolated lungs were apparent by 21 days of MCT treatment. The magnitude of the changes in all of these parameters increased with duration of treatment. After 28 days of treatment biliary indocyanine green excretion was decreased and plasma glutamic pyruvic transaminase activity was slightly elevated. Twenty-eight days of treatment also resulted in elevated blood urea nitrogen, decreased accumulation of p -aminohippuric acid by kidney slices, and increased accumulation of tetraethylammonium by kidney slices. Thus, lung, liver, and kidney are each affected by this MCT treatment regimen, and functional effects on lung precede effects on other tissues.

Nephrotoxicity and hepatotoxicity of chloroform in mice: Effect of deuterium substitution

Chloroform (CHCl3) produces renal and hepatic damage in humans and experimental animals. Deuterium-labeled chloroform (CDCl3) has been reported to be less hepatotoxic than CHCl3 in rats. However, this isotope effect has not been determined in other species or in extrahepatic tissues. In this investigation, the effect of deuterium substitution on the nephrotoxicity and hepatotoxicity of CHCl3 was quantified in male ICR mice. Renal and hepatic damage were determined 24 h after administration on various doses of CHCl3 or CDCl3. Liver damage was estimated by measuring serum glutamic-pyruvic transaminase (SGPT) activity. Nephrotoxicity was evaluated by measuring blood urea nitrogen (BUN) and in vitro renal cortical accumulation of p-aminohippurate (PAH) and tetraethylammonium (TEA). Dose-related hepatotoxicity and nephrotoxicity were observed after administration of CHCl3 and CDCl3. CDCl3 produced less liver damage than CHCl3 in mice, suggesting that mouse liver metabolizes CHCl3 by the same mechanism as rat liver. CDCl3 was also less toxic to kidneys than CHCl3, suggesting that the kidney may metabolize CHCl3 in the same manner as the liver

Metabolic heterogeneity of the proximal and distal kidney tubules.

Proximal and distal tubule suspensions were prepared from kidneys of Sprague-Dawley rats by an isolation procedure on a Percoll gradient. The marker enzymes alkaline phosphatase (brush border) and hexokinase (cytoplasmic) as well as p-aminohippurate transport capacity, gluconeogenic activity and electron microscopy were used to characterize the two kidney tubule suspensions. The results of this study indicate that cytochrome P-450 is localized to the proximal tubular cells and that the O-deethylation of 7-ethoxycoumarin was higher in the proximal than distal fraction. Both proximal and distal tubules showed glucuronidation and deacetylation capacities and a relatively equal distribution of non-protein sulfhydryls. These studies demonstrate metabolic heterogeneity of the nephron, the proximal tubule being the main site of renal xenobiotic metabolism. Understanding of metabolic heterogeneity of proximal and distal kidney tubules should provide important information regarding cell specific mechanisms of nephrotoxicity.

Induction of drug-metabolizing enzymes and toxicity of trans-stilbene oxide in rat liver and kidney

The effect of trans-stilbene oxide (TSO) on organ function and morphology and on drug-metabolizing enzymes was determined in male Sprague-Dawley rats. TSO (300 or 600 mg/kg) was administered i.p., once daily for 5 consecutive days. At a dose of 3400 mg/kg, TSO did no alter body weight, but increased liver weight. The higher dose (600 mg/kg) markedly decreased body weight. TSO treatment (300 mg/kg) induced several drug-metabolizing enzymes. Epoxide hydrolase activity was enhanced in the liver, kidney and lung. In contrast, arylhydrocarbon hydroxylase activity was not significantly altered. Glutathione S-transferase activity, with 1-chloro-2,4-dinitrobenzene as substrate, and uridine diphosphoglucuronyl transferase activity, with p-nitrophenol as substrate, were also increased in the liver and kidney after TSO treatment. It appears that TSO induces hepatic and renal enzyme activities in a similar manner. Treatment with the higher dose of TSO depressed accumulation of p-amino-hippurate by renal cortical slices and increased blood urea nitrogen concentration. Histological examination of kidney sections after treatment with TSO revealed no abnormality. The lower dose led to negligible alteration in liver and the higher dose resulted in mild to moderate hepatic cellular.

Postnatal development of renal and hepatic drug-metabolizing enzymes in male and female Fischer 344 rats

Abstract Postnatal development of renal and hepatic drug-metabolizing enzymes (DME) has been determined in male and female Fischer-344 (F344) rats. Arylhydrocarbon hydroxylase (AHH) epoxide hydrolase (EH), glutathione S-transferase (GST) and uridine diphosphoglucuronyltransferase (UDPGT) activities were measured at 7, 14, 28, 42, 63 and 84 days after birth. No sex-dependent difference was found in renal AHH activity. In contrast, male hepatic AHH increased sharply after 28 days while female hepatic AHH activity declined. EH and GST activities in the kidney increased slightly during maturation. Hepatic EH activity rose after birth and reached a peak at 42 days. Renal UDPGT activity was low in the first two weeks of life and then rapidly increased to the adult value by 42 days. In contrast, hepatic UDPGT activity was high at birth and declined during maturation. These results demonstrate that the patterns of postnatal development of renal DME in F344 rats differed from that of liver DME. These differences may be important in the determination of the susceptibility of kidney and liver to toxic chemicals.

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.

Effect of phenobarbital on cephaloridine toxicity and accumulation in rabbit and rat kidneys.

Abstract Cephaloridine causes necrosis of renal proximal tubules in humans and laboratory animals. This antibiotic nephrotoxicity in rats has been shown to be reduced by mixed-function oxidase (MFO) inhibitors such as piperonyl butoxide and cobaltous chloride. The purpose of this study was to determine the effect of phenobarbital, a MFO inducer, on cephaloridine nephrotoxicity in rats and rabbits. Phenobarbital induced rabbit renal MFO activities and also potentiated cephaloridine toxicity in rabbit kidneys. In contrast, a similar treatment with phenobarbital produced little effect on rat renal MFO activities and did not alter cephaloridine nephrotoxicity in rats. These results suggested that cephaloridine may have to be bioactivated within the kidney prior to producing toxicity. However, a higher renal cortical concentration of cephaloridine was detected in phenobarbital-treated rabbits. This higher concentration appeared to be due to a greater ability of renal cortical cells to accumulate cephaloridine. Therefore, rather than as a result of enzyme induction, the potentiating effect of phenobarbital on cephaloridine nephrotoxicity might be due to the increased renal cortical accumulation of the parent drug, cephaloridine.