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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.

The aminoglycosides gentamicin, netilmicin and tobramycin were each administered (30 mg/kg/day) to male Wistar rats for 21 days. At 7, 14 and 21 days rats were anesthetized and renal clearances of inulin and egg-white lysozyme were quantified. Plasma concentration of lysozyme varied between 20 and 120 mg/liter in control and aminoglycoside treated rats. Inulin clearance (GFR) averaged 0.96 ml/min/kidney in control rats. Whereas GFR decreased to an average value of 0.47 ml/min/kidney in gentamicin treated rats, GFR did not fall in tobramycin treated rats, averaging 0.97 ml/min/kidney over the entire treatment period. In netilmicin rats GFR declined to 0.53 ml/min/kidney after 7 days of treatment and then increased to 0.78 ml/min/kidney after 14 days and 21 days of treatment. Reabsorption of lysozyme averaged about 94% of the filtered load in control rats. Reabsorption of lysozyme decreased in gentamicin treated rats to about 58% after 7 days and 14 days of treatment and increased to 79% after 21 days of treatment. After tobramycin reabsorption of lysozyme decreased to about 67% after 7 days of treatment and increased to 85% after 14 days and 21 days of treatment. Reabsorption of lysozyme remained unchanged when compared to controls over the entire treatment period in netilmicin treated rats. Thus, gentamicin reduced both GFR and renal reabsorption of lysozyme. Netilmicin reduced GFR somewhat without altering lysozyme reabsorption whereas tobramycin compromised lysozyme reabsorption without altering GFR. These differences might suggest differences in site(s) of action of various aminoglycosides.

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.

Strain differences in susceptibility of rats to acetaminophen (APAP)-induced nephrotoxicity have been previously reported. Young adult male Fischer-344 (F-344) rats are susceptible whereas weight-matched Sprague-Dawley (SD) rats are not susceptible to APAP nephrotoxicity. The present study was designed to evaluate the role of pharmacokinetics in strain-dependent APAP nephrotoxicity. Age-matched (2-month-old) male F-344 and SD rats received 250-750 mg APAP/kg, i.v., or 0-1000 mg APAP/kg, i.p. Pharmacokinetic variables were evaluated following i.v. APAP and 24 h urinary excretion of APAP and major metabolites was determined following both i.v. and i.p. administration of APAP. Following i.p. administration, nephrotoxicity was observed only in F-344 rats following 1000 mg APAP/kg; SD rats were not susceptible to APAP-induced nephrotoxicity. In contrast, nephrotoxicity did not occur in either F-344 or SD rats administered APAP i.v. Pharmacokinetic variables (volume of distribution, apparent systemic clearance, and apparent terminal half-life) of APAP were similar in F-344 and SD rats. No striking differences in the pattern of specific urinary metabolites were observed between F-344 and SD rats treated with i.p. or i.v. APAP. Thus, strain differences in APAP-induced nephrotoxicity do not appear to be due to differences in pharmacokinetics or major pathways of APAP metabolism.

Age-related differences in susceptibility to cephaloridine nephrotoxicity were evaluated in male Fischer-344 rats. Rats, 2.5, 4, 10-12 and 27-29 months old, were administered a single intraperitoneal dose of cephaloridine and renal function evaluated 24 h later. Susceptibility to cephaloridine-induced nephrotoxicity was age-related. Older rats (10-12 and 27-29 months) were the most susceptible to cephaloridine nephrotoxicity as indicated by a dose-related increase in relative kidney weight, elevation in blood urea nitrogen concentrations and a diminished capacity of renal cortical slices to accumulate the organic anion, p-aminohippurate (PAH) and the organic cation, tetraethylammonium (TEA). Impaired renal function following cephaloridine treatment was not detected in 2.5-month-old, apparent to a slight extent in 4-month-old, and most pronounced in 10-12- and 27-29-month-old rats. Serum and renal cortical concentrations of cephaloridine tended to be greater in older rats compared to that of young adults. Thus, the enhanced susceptibility of older rats to cephaloridine nephrotoxicity may be related in part to the increased renal cortical accumulation of cephaloridine.

The polycationic aminoglycoside gentamicin has been reported to compete with other aminoglycosides and cationic compounds for uptake into renal tubular cells at brush border membranes and during subsequent endocytosis. Gentamicin has also been reported to decrease the activity of lysosomal proteolytic enzymes in the rat kidney. In vivo and in vitro experiments were carried out to determine the effect of acute exposure to gentamicin on renal handling of the cationic low molecular weight protein, lysozyme. Thirty or 60 mg/kg of gentamicin was given to male Wistar rats (250-300 g) intravenously or isolated rat kidneys were perfused with gentamicin concentrations of 0.25, 0.50, 1.0 and 2.5 mg/ml. Subsequently, clearances of lysozyme (CLY) and inulin (GFR, glomerular filtration rate) were measured in the intact rat and in the isolated perfused rat kidney. The glomerular sieving coefficient of lysozyme was determined in control and gentamicin perfused kidneys after complete inhibition of tubular lysozyme reabsorption by sodium iodoacetate. Renal degradation of 125I-labelled lysozyme was quantified in control and gentamicin perfused kidneys by measuring the release of [125I] monoiodotyrosine to the perfusate. The glomerular sieving coefficient of lysozyme increased in kidneys perfused with gentamicin from a control value of 0.8-1.0. A dose-dependent increase of the ratio CLY/GFR in intact rats treated with gentamicin and dose-dependent decrease of percentage reabsorption of lysozyme in the isolated perfused kidneys demonstrate inhibition of renal reabsorption of lysozyme by gentamicin. Perfusion of kidneys with 0.25 mg/ml gentamicin reduced renal degradation of lysozyme to about 50% after 2 h perfusion; at gentamicin concentrations of 0.5 mg/ml and higher almost all degradation of lysozyme was inhibited. Thus, acute exposure to gentamicin causes impairment of filtration, tubular reabsorption and catabolism of the protein lysozyme, effects which are due to pharmacological interactions between the molecules of the 2 cations gentamicin and lysozyme.

Isolated perfused rat kidneys were used to determine the contribution of filtration and tubular transport of cisplatin to its nephrotoxicity. Perfusion of kidneys with 0.5 mM cisplatin concomitantly reduced tubular reabsorption of electrolytes and glomerular filtration rate in a time-dependent manner. These renal functional changes were similar to those obtained following in vivo cisplatin treatment (10 mg/kg). In vitro exposure to cisplatin reduced the renal clearance of organic ions without reducing renal perfusate flow, suggesting that renal hemodynamic changes do not mediate cisplatin-induced proximal tubular dysfunction. Inhibition of organic ion transport also was observed in non-filtering perfused kidneys treated with 0.5 mM cisplatin, implying that filtration of cisplatin is not a prerequisite for induction of toxicity. These data also suggest that cisplatin transport from a basolateral site may be important in the development of acute nephrotoxicity.

cis-Dichlorodiammineplatinum (cis-Pt) is a heavy metal complex used in cancer chemotherapy. Since this drug has been shown to induce hyperglycemia in rats, these studies were initiated to elucidate the effects of cis-Pt on carbohydrate tolerance and insulin and glucagon secretion. Two days following i.v. cis-Pt (2.5 or 7.5 mg/kg, 5 ml/kg) or vehicle administration to male F-344 rats, plasma glucose, immunoreactive insulin (IRI) and glucagon (IRG) concentrations were determined in the basal state and serially following a glucose load (2 g/kg, i.p.). Since cis-Pt induces a dose-related anorexia, a pair-fed control group was also studied. Administration of 7.5 mg/kg cis-Pt was associated with plasma glucose concentrations 2.5-5 times greater than ad-libitum and pair-fed controls at every time point during the 2-h glucose tolerance test. Although basal plasma IRI concentrations of the 7.5-mg/kg group were comparable to ad-libitum fed controls, they were significantly greater than those of pair-fed partners. Furthermore, the appropriate IRI response to a glucose stimulus observed in both controls and the 2.5-mg/kg group was absent in the 7.5-mg/kg group. Basal plasma IRG concentrations of the 7.5-mg/kg group were approximately 3-4 times greater than ad-libitum and pair-fed controls and were not suppressed following a glucose load. These results suggest that cis-Pt induces marked glucose intolerance in association with an impaired IRI response and abnormal glucagon response to a glucose stimulus.

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.

High doses of cephaloridine produce necrosis of renal proximal tubular cells and this nephrotoxicity has been shown to be reduced by piperonyl butoxide (a mixed-function oxidase inhibitor) in rats and rabbits, and potentiated by phenobarbital (a mixed-function oxidase inducer) in rabbits but not rats. Phenobarbital is known to increase rabbit but not rat renal mixed-function oxidase activities; however, several other compounds such as polybrominated biphenyls (PBB), trans-stilbene oxide (TSO) and beta-naphthoflavone (BNF) have been shown to induce renal enzyme activities in rats. Thus, it was of interest to determine the effects of PBB, TSO and BNF on cephaloridine toxicity in Fischer 344 rats. Nephrotoxicity was estimated by measuring alterations in the kidney-to-body weight ratio, blood urea nitrogen and accumulation of p-aminohippurate (PAH) and tetraethylammonium by renal cortical slices. Hepatotoxicity was quantified as changes in serum glutamic pyruvic transaminase (SGPT) activity. Cephaloridine produced only minor changes in SGPT activity. Animals fed diet supplemented with 100 ppm of PBB for 10 days became less susceptible to cephaloridine nephrotoxicity. Similarly, pretreatment of animals with TSO (300 mg/kg) or BNF (100 mg/kg) for 4 days decreased cephaloridine toxicity. Thus, these results suggest that induction of renal drug-metabolizing enzyme activities by these 3 inducers may enhance some detoxification pathway(s) which convert cephaloridine to a non-toxic metabolite(s). Alternatively, treatments with these inducers may alter cephaloridine pharmacokinetics and decrease renal cortical accumulation of cephaloridine.

Subacute (20 days) oral administration of hexachlorobenzene (HCB) or the organohalide mixtures polybrominated biphenyls (PBB) or polychlorinated biphenyls (PCB) greatly increased th susceptibility of male rats to the toxic effects of carbon tetrachloride (CCl4). CCl4-induced acute growth retardation, renal tubular functional impairment and hepatocellular necrosis were quantitatively greater in rats pretreated with the aromatic organohalides than in naive rats. Pretreatment with HCB, PBB or PCB also reduced survival after i.p. administration of CCl4 and increased the severity of morphological liver injury. Despite functional impairment, only minor histological alterations attributable to CCl4 were detected in the kidney. CCl4 as well as HCB, PBB or PCB increased the lipid content of the liver, but not the kidney. CCl4 administration depressed energy-dependent accumulation of organic ions by renal cortical slices in vitro in a dose-dependent manner and increased the basal rate of respiration of renal cortical tissue in vitro. It is concluded from these results that exposure to certain commercial aromatic organohalides can greatly alter organ response to toxicants such as CCl4.

Male Fischer 344 rats were killed at various times after single or multiple treatments with polybrominated biphenyls (PBB), polychlorinated biphenyls (PCB), sodium phenobarbital (NaPB) or 3-methylcholanthrene (3MC). p-Chloro-N-methyl-aniline N-demethylase (PCNMA) and aryl hydrocarbon hydroxylase (AHH) activities were determined in the 14 000 g supernatant fraction (postmitochondrial supernate, PMS) of renal, testicular and hepatic homogenates. Cytochrome P-450 (p-450) concentrations were determined in the 100 000 g pellet fractions of the same homogenates and the effects of enzyme induction on the sensitivities of AHH in PMS to inhibition by alpha-napthoflavone (ANF) and metyrapone (MET) in vitro were determined. Single treatments with PBB or PCB induced hepatic P-450 only, while multiple treatments with PBB, PCB or 3MC induced both renal and hepatic P-450; NaPB induced only hepatic P-450, while testicular P-450 concentration was unaffected by the inducers. Treatments with PBB, PCB or 3MC shifted the Soret maxima of renal and hepatic dithionite-reduced P-450 difference spectra to shorter wavelengths. Multiple treatments with PBB, PCB or 3MC increased renal and hepatic AHH activities, but NaPB induced hepatic AHH only. Renal AHH activity was increased more rapidly than hepatic AHH after a single treatment with PBB, PCB or 3MC and returned more rapidly to control. The renal AHH induced by PBB and PCB, like that induced by 3MC, was more sensitive to inhibition by ANF in vitro than was renal AHH from naive rats. Hepatic AHH induced by PBB and PCB, unlike that induced by NaPB or 3MC, exhibited no net alterations in sensitivities to the inhibitory effects of ANF or MET. Testicular AHH activity was not induced by PBB, PCB , NaPB or 3MC. Multiple treatments with PBB, PCB or NaPB increased hepatic, but not renal or testicular PCNMA activities. The organ-specificity and time-dependency of the effects of PBB, PCB, NaPB and 3MC on P-450 concentrations and AHH activities suggest that drug metabolism in kidney, testis and liver are regulated by separate control mechanisms. It may be possible to exploit such differences in organ response to enzyme inducers as tools with which to discern the roles of local metabolism in renal and testicular chemical injury.

A marked species difference exists in the induction of renal and hepatic mixed function oxidase (MFO) activity between rats and rabbits. However, little is known about MFO induction in these organs from other laboratory animals. Male Golden Syrian hamsters and male Hartley guinea pigs were administered phenobarbital (PB) or beta-napthoflavone (BNF) at 70 and 40 mg/kg, respectively, as daily i.p. injections for 4 days. Polybrominated biphenyl (PBB) (Firemaster BP-6) was given as a single i.p. injection (50 mg/kg). Hamster hepatic microsomal ethoxyresorufin-O-deethylase (EROD) and benzphetamine-N-demethylase (BPND) were selectively induced by BNF and PB, respectively. PBB administration induced both hamster hepatic EROD and BPND. In contrast, hepatic microsomal MFO activity from the guinea pig was inducible by PB, PBB and BNF. Renal microsomal MFO activity in both species was inducible by BNF and PBB as arylhydrocarbon hydroxylase and EROD were induced approximately 10-fold. On the other hand, hamster BPND was induced by PB whereas guinea pig MFO activity was unaffected. Total renal cytochrome P-450 content was not affected by any of these inducers in either species. These data demonstrate selective patterns of induction in both hamster and guinea pig liver and kidney suggesting the involvement of multiple forms of cytochrome P-450.

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.