Protein degradation in the kidney occurs mainly in lysosomes, organelles which may also accumulate nephrotoxic chemicals. The goal of this study was to evaluate the effects of intracellular accumulation of gentamicin, cephaloridine and cisplatin on lysosomal digestion of the protein lysozyme. Gentamicin (15 or 30 mg/kg/day for 3 or 5 days), cisplatin (2.5 or 5 mg/kg) or cephaloridine (500, 1000, 2000 or 2500 mg/kg) was administered ip to male Wistar rats. The main site of the nephrotoxic effects of these compounds was the proximal tubule where these agents differentially affected S1, S2 and/or S3 segments. A 2- and 4-fold increase of the excretion of N-acetyl-beta-D-glucosaminidase (NAG) was observed in the urine from cisplatin- and gentamicin-treated rats, respectively; no change in enzyme excretion occurred after cephaloradine. One hour prior to sacrifice, rat were given 0.3 mg of unlabelled lysozyme in combination with 125I-lysozyme in 0.3 mL saline. Renal cortical slices were prepared and incubated for 15, 30, 60 and 90 min. Release of trichloroacetic acid (TCA) soluble radioactivity into the medium was assumed to quantify lysosomal degradation of lysozyme. Accumulation of p-amino-hippurate (PAH) in renal cortical slices and changes in blood urea nitrogen (BUN) concentration were used as indices of renal damage. TCA-soluble radioactivity increased in the medium from kidney slices from control rats to 50% of the total radioactivity after 90 min incubation. In gentamicin-treated rats, lysozyme degradation was significantly decreased by doses of 15 and 30 mg/kg/day after 3 and 5 days of exposure in the absence of any changes in BUN or PAH accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

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

Animals↗

PubMedDate not supplied

Effect of polybrominated biphenyls on hepatic microsomal metabolism of estrogens and uterotropic action of administered estrogen in rats.

Perinatal exposure to polybrominated biphenyls (PBBs) increased the hepatic microsomal metabolism of estradiol, estrone, and ethynylestradiol in vitro. Pretreatment with PBBs decreased the effect of estradiol administered exogenously on uterine estrogen cytosolic receptor concentration. The effect of exogenous estradiol on uterine weight and uterine RNA content was also reduced by perinatal exposure to PBBs. Therefore, metabolism of estrogens is altered by PBBs.

Animals↗

PubMedDate not supplied

Pharmacology and pharmacokinetics of LEX 032, a bioengineered serpin: the first of a potential new class of drugs.

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Animals↗

PubMedDate not supplied

Role of pharmacokinetics and metabolism in the enhanced susceptibility of middle-aged male Sprague-Dawley rats to acetaminophen nephrotoxicity.

Middle-aged male Sprague-Dawley (SD) rats (9-12 months) are more susceptible to acetaminophen (APAP)-induced nephrotoxicity than are young (2-3 months) adult males. The present studies were designed to evaluate the role of pharmacokinetics and renal and hepatic metabolism of APAP in age-dependent nephrotoxicity. Following 750 mg/kg APAP, ip, a nephrotoxic dosage in 12-month-old but not 3-month-old rats, renal cortical APAP concentrations were significantly greater in 12-month-old compared with 3-month-old SD rats at 3, 4, and 6 hr after treatment. Renal medullary APAP concentrations in 12 month-old rats were significantly greater than in 3-month-old rats at 2, 3, and 5 hr after treatment. Serum APAP concentrations were significantly elevated in 12-month-old compared with 3-month-old rats from 2 through 5 hr after APAP (750 mg/kg ip). However, APAP tissue/serum concentration ratios were similar in 3- and 12-month-old rats, indicating that differences in tissue concentration were secondary to increased serum concentrations in older rats. Conjugated APAP metabolites in blood were similar in 3- and 12-month-olds during the initial 2-3 hr after 750 mg/kg APAP, ip, but began to accumulate in 12-month-old but not 3-month-old rats within 6-8 hr after APAP administration, perhaps secondary to declining renal function. After 500 mg/kg APAP, iv, blood APAP concentrations were markedly elevated in 12-month-old compared with 3-month-old rats during the entire course of the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗