Biomedical subjects

J B Hook

Publications and source records attributed to J B Hook.

At least 55 records · Page 3Linked to original sources

PubMed1984

Effect of dietary trans-stilbene oxide on hepatic and renal drug-metabolizing enzyme activities and bromobenzene-induced toxicity in male Sprague-Dawley rats.

The effect of dietary trans-stilbene oxide (TSO) on hepatic and renal xenobiotic metabolizing-enzyme activities and bromobenzene-induced toxicity was quantified in adult male Sprague-Dawley rats. Rats were fed a regular diet or the same diet supplemented with 2.5 g TSO/kg diet for 10 days. TSO treatment did not alter hepatic or renal arylhydrocarbon hydroxylase activity, but significantly increased glutathione S-transferase and uridine diphosphoglucuronyl transferase activities in both organs. In addition, TSO increased hepatic, but not renal, epoxide hydrolase activity. The same treatment did not produce adverse effects on renal or hepatic functions, but markedly potentiated bromobenzene hepatotoxicity. A single dose of bromobenzene (0.2 ml/kg) caused a slight increase in serum glutamic pyruvic transaminase (SGPT) activity and minor hepatic necrosis in animals fed the control diet; the same dose of bromobenzene markedly increased SGPT activity and produced severe hepatic necrosis in the TSO-fed animals.

Animals↗

PubMed1984

Nephrotoxicity of bromobenzene in mice.

I.p. administration of bromobenzene to male mice at doses ranging from 0 to 9.4 mmol/kg resulted in a dose-dependent increase in blood urea nitrogen (BUN) and serum glutamic-pyruvic transaminase (SGPT) activity and a decrease in renal cortical accumulation of para-aminohippurate (PAH) and tetraethylammonium (TEA). Induction of renal and hepatic mixed-function oxidases by beta-naphthoflavone (BNF) did not result in any alterations in the hepatotoxic or nephrotoxic response to bromobenzene. Renal and hepatic non-protein sulfhydryl (NPSH) concentrations were decreased significantly 1 h after administration of bromobenzene (7.5 mmol/kg) and were maximally depleted in both organs to 18% of control after 7 h. Depletion of renal NPSH by bromobenzene was dose-dependent up to 9.4 mmol/kg. Treatment of mice with diethyl maleate (DEM) (0.6 ml/kg) 60 min prior to bromobenzene administration resulted in greater hepatotoxicity, evidenced by increased SGPT, while renal toxicity was unchanged. These data demonstrate that large doses of bromobenzene produce functional alterations in the kidney.

Animals↗

PubMed1984

Metabolism and pharmacokinetics of acetaminophen in a severely poisoned young child.

A 1-year-old child with severe acetaminophen (APAP) poisoning after ingestion of 10 gm APAP demonstrated central nervous system depression, shock, hypothermia, and metabolic acidosis. There was dramatic improvement during treatment with intravenously administered N-acetylcysteine (NAC) and hemodialysis, and the patient recovered without sequelae. A detailed study of APAP metabolism was carried out during the initial 72 hours after ingestion. APAP-sulfate and APAP-glucuronide accounted for 29% and 33%, respectively, of total drug in urine, whereas cysteine and NAC conjugates accounted for only 12%. The low incidence of severe toxicity in children after overdoses of APAP may be related to greater capacity to metabolize APAP via a nontoxic pathway.

Acetaminophen↗

PubMed1984

Effects of aminoglycosides on glomerular ultrastructure.

Effects of the aminoglycosides, gentamicin, netilmicin and tobramycin (30 mg/kg/day X 7, i.p.), on glomerular ultrastructure were determined in male Wistar rats. Glomerular ultrastructure was studied by scanning and transmission electron microscopy. The average number of capillary endothelial fenestrae per 5 microns of capillary wall decreased from a control value of 10.8 to 8.2 and 8.1 in gentamicin- and tobramycin-treated rats, respectively, as shown by transmission electron microscopy (TEM). Scanning electron microscopy (SEM) showed that the density of endothelial fenestrae decreased to about 80% of control in gentamicin- and tobramycin-treated rats. In addition, gentamicin and tobramycin produced a marked reduction in the number of granulated myoepithelioid++ cells of the juxtaglomerular apparatus. Netilmicin appeared to have no effect on glomerular ultrastructure. Both TEM and SEM, indicate that the nephrotoxic aminoglycosides gentamicin and tobramycin alter the ultrastructure of the fenestrated endothelia of the glomerular capillaries. These ultrastructural changes appear to be correlated to the impairment of the glomerular permeability for different compounds.

Aminoglycosides↗

PubMed1984

Renal ultrastructural and biochemical injuries induced by aminoglycosides.

Aminoglycoside-induced proteinuria may result from general renal damage or may reflect alterations in specific steps in the renal handling of proteins. To differentiate between the two possibilities, experiments were designed to quantify the effects of nephrotoxic doses of gentamicin, tobramycin and netilmicin in the intact rat, isolated perfused rat kidney (IPK) and kidney slices using the cationic low molecular weight protein lysozyme as a model protein. Each aminoglycoside was administered IP to male Wistar rats (15 or 30 mg/kg/day) for 5 or 7 days. Scanning and transmission electron microscopy indicated that gentamicin and tobramycin induced a decrease in the number and diameter of endothelial fenestrae and degranulation of the myoepithelioid cells of the juxtaglomerular apparatus. Concurrently, gentamicin and tobramycin decrease the glomerular sieving coefficient of lysozyme from 0.8 to 0.6 and 0.5, respectively. Netilmicin did not affect the percentage reabsorption of lysozyme whereas gentamicin and tobramycin induced a 50% decrease in lysozyme reabsorption by the IPK. Gentamicin and tobramycin decreased equally lysozyme degradation by the IPK; this decrease was time- and dose-dependent when evaluated in slices from renal cortex. Perfusion of rat kidneys with gentamicin induced a dose-dependent decrease in reabsorption and catabolism of lysozyme. In conclusion, these studies demonstrate that polycationic aminoglycosides alter ultrastructure and glomerular permeability, tubular reabsorption and intracellular digestion of proteins.

Absorption↗

PubMed1984

Chemically induced nephrotoxicity: role of metabolic activation.

Renal xenobiotic metabolism can result in production of electrophiles or free radicals that may covalently bind macromolecules or initiate lipid peroxidation. The mechanisms of renal xenobiotic metabolism may vary in different anatomical regions. Kidney cortex contains a cytochrome P-450 system while medulla contains a prostaglandin endoperoxidase. Recently cysteine conjugated-lyase has been implicated in production of reactive intermediates. Metabolic activation may be amplified by accumulation of xenobiotics within renal cells due to tubular concentrating and/or secretory mechanisms. Additionally, renal xenobiotic detoxicification can occur by conjugation with glucuronide, sulfate or glutathione.

Acetaminophen↗

PubMed1984

Biochemical interactions and nephrotoxicity.

To understand the nephrotoxicity of xenobiotics, the species, strain, sex, and the presence of other chemicals must be considered. This review has considered the importance of these factors in determining the nephrotoxic liability of a drug. For example, cephaloridine is more nephrotoxic in rabbit than rats and is least nephrotoxic in mice. This species-dependent susceptibility to cephaloridine nephrotoxicity appears to be related to the degree in which cephaloridine depletes renal cortical glutathione. Additionally, only male mice of certain strains are susceptible to chloroform-induced nephrotoxicity. Lastly, the presence of certain ketones or ketogenic substances such as acetone and hexane enhance chloroform-induced nephrotoxicity in male Sprague-Dawley rats. Knowing which factors can enhance or limit nephrotoxicity of drugs will lend to a better understanding of the mechanism of these toxicities as well as to design compounds with lesser toxicities.

Animals↗

PubMed1984

cis-Dichlorodiammineplatinum nephrotoxicity in rats of different ages.

In 5-, 15-, 30-, and 60-day-old rats there was a distinct decrease of body weight 24 hours after a single i.p. injection of cis-dichlorodiammineplatinum (CDDP) over a dose range from 0.25 to 2.0 mg/100 g b.w.t. Compared with a control group the kidney weights appeared nearly unchanged. The increase of blood urea nitrogen (BUN) concentrations following CDDP treatment was dose dependent and more profound in 5- and 15-day-old rats than in older animals. In higher doses, CDDP impaired the renal concentrating ability in rats of all age groups as reflected in a significant increase in urine volume with only a slightly increased renal sodium excretion. Following CDDP treatment there was a moderate proteinuria. In 30- and 60-day-old rats the renal excretion of p-aminohippurate (PAH) was more reduced by CDDP compared to younger rats.

Age Factors↗

PubMed1983

Acetaminophen nephrotoxicity in the rat. Renal metabolic activation in vitro.

High doses of acetaminophen (APAP) result in hepatic centrilobular and renal cortical necrosis in man and the F344 rat. Hepatic necrosis is considered to be due to the generation of an arylating intermediate via a microsomal cytochrome P-450 dependent system. Renal microsomes also metabolize APAP to an arylating intermediate via a P-450 dependent mechanism. Thus, at least part of the renal damage from APAP may be due to a biochemical mechanism similar to that in liver. Additionally, APAP is deacetylated to p-aminophenol (PAP) in renal and hepatic cytosol and microsomes. Previous results demonstrated that PAP may be activated in renal microsomes via an NADPH-independent mechanism. Therefore, significant metabolic activation of APAP in the kidney may occur subsequent to deacetylation. Covalent binding of [ring-14C]APAP to renal subcellular fractions was used to substantiate this hypothesis. Under appropriate incubation conditions, enzymatic NADPH-independent covalent binding of [ring-14C]APAP could be demonstrated in renal microsomes but not in 100,000g supernatant fractions. Combination of these subcellular fractions resulted in greater covalent binding of [ring-14C]APAP than in the individual subcellular fractions alone. Addition of glutathione, bis(p-nitrophenyl)phosphate (a deacetylase inhibitor), or PAP inhibited this covalent binding. In contrast, NADPH-independent covalent binding of [ring-14C]APAP could not be demonstrated in any combination of hepatic subcellular fractions. Experiments comparing [ring-14C]APAP and [acetyl-14C]APAP covalent binding to renal 10,000g supernatant fractions indicate that the compound which binds to renal macromolecules is derived from PAP. Thus, these results are consistent with the hypothesis that APAP can be metabolically activated in the kidney after deacetylation to PAP.

Acetaminophen↗

PubMed1983

Mechanism of chloroform nephrotoxicity. I. Time course of chloroform toxicity in male and female mice.

Chloroform (CHCl3) nephrotoxicity in male mice could be detected as early as 2 hr after CHCl3 administration (250 microliter/kg, sc) as decreased ability of renal cortical slices to accumulate p-aminohippurate (PAH) and tetraethylammonium (TEA). The decrease was preceded and paralleled by a reduction of renal cortical nonprotein sulfhydryl (NPSH) concentration, an index of tissue reduced glutathione concentration. Histologic alterations were not observed until NPSH concentrations and PAH and TEA accumulation had reached the nadir, 5 hr after CHCl3 administration. Female mice exhibited no evidence of nephrotoxicity to CHCl3 even when the dose was increased to 1000 microliter/kg or when pretreated with diethyl maleate to reduce renal cortical NPSH concentrations prior to CHCl3 injection. The extent of hepatotoxicity was similar in male and female mice and decreases of hepatic NPSH concentrations also were detected by 1.5 hr after CHCl3 administration. The rapid response of the kidney to CHCl3 toxicity in male mice and the similarity of liver toxicity in both sexes suggests that nephrotoxicity occurs independently of hepatotoxicity. Furthermore, the ability to detect these early changes in vivo following CHCl3 administration may permit the development of an in vitro model to evaluate the mechanism of CHCl3 nephrotoxicity.

Animals↗

PubMed1983

Mechanism of chloroform nephrotoxicity. II. In vitro evidence for renal metabolism of chloroform in mice.

Preincubation of renal cortical slices with chloroform (CHCl3) from male, but not female, mice resulted in a subsequent decrease of the ability of the slices to accumulate the organic ions, p-aminohippurate (PAH) and tetraethylammonium (TEA). These sex-related differences, the time required for manifestation of this effect (60 to 90 min), and the concentration dependency (0 to 50 mumol, 0 to 4 microliter CHCl3) were similar to in vivo observations on CHCl3 nephrotoxicity in mice. Furthermore, an equimolar concentration of deuterated CHCl3 (CDCl3) in vitro was less effective than CHCl3 in decreasing PAH and TEA accumulation in male renal cortical slices. The effects of CHCl3 on PAH and TEA accumulation could be diminished or blocked by preincubation with CHCl3 in the presence of carbon monoxide or at 0 degrees C, respectively. The nephrotoxicity of CHCl3 in vitro was increased in renal cortical slices from male mice pretreated with diethyl maleate. Thus, this in vitro model with mouse renal cortical slices and the sex-related differences in CHCl3 nephrotoxicity suggests that the kidney may metabolize CHCl3 in situ to a nephrotoxic metabolite.

Animals↗

PubMed1983

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.

7-Alkoxycoumarin O-Dealkylase↗

PubMed1983

Effects of age and sex on hexachloro-1,3-butadiene toxicity in the Fischer 344 rat.

Effects of age and sex on hexachloro-1,3-butadiene (HCBD) nephrotoxicity were determined 24 hours after a single dose (0, 25, 50, 100 or 200 mg/kg) in 28- and 63-day-old Fischer 344 rats. HCBD treatment significantly increased the kidney to body weight ratio but had little effect on the liver to body weight ratio. The 28-day-old rats were more susceptible to HCBD nephrotoxicity judged by elevated blood urea nitrogen, decreased renal cortical accumulation of p-aminohippurate and tetraethylammonium. Adult female rats (63-day-old) appeared to be more susceptible to HCBD nephrotoxicity than males at the low dose (50 mg/kg).

Aging↗

PubMed1983

Acetaminophen nephrotoxicity in the rat. I. Strain differences in nephrotoxicity and metabolism.

Acetaminophen (APAP) produced renal necrosis restricted to the straight segment of the proximal tubule in Fischer 344 (F344) rats but not in Sprague-Dawley (SD) rats. APAP-induced renal functional changes (elevation in blood urea nitrogen and reduction in the accumulation of p-aminohippurate by renal cortical slices) also correlated with strain-dependent histopathological changes. Such strain differences have been attributed to differences in renal P-450 activation of APAP or the deacetylation of APAP to the nephrotoxic metabolite, p-aminophenol (PAP). Kidneys from F344 rats displayed greater concentrations of P-450 and greater ethoxycoumarin-o-deethylase activity than kidneys from SD rats. However, covalent binding of [ring-14C]APAP to renal and hepatic microsomal protein in vitro was similar for both SD and F344 rats. Deacetylation of APAP to PAP was similar in renal and hepatic homogenates from SD and F344 rats. Furthermore, isolated kidneys from SD and F344 rats perfused with APAP excreted PAP at similar rates. PAP excretion, over a 24-hr period following APAP administration, was greater in F344 rats than in SD rats only at the highest dose (900 mg/kg) of APAP. Thus, strain differences in APAP-induced nephrotoxicity apparently cannot be attributed to differences in P-450 activation of APAP or in deacetylation to the nephrotoxic metabolite, PAP.

Acetaminophen↗

PubMed1983

Acetaminophen nephrotoxicity in the rat. II. Strain differences in nephrotoxicity and metabolism of p-aminophenol, a metabolite of acetaminophen.

Acetaminophen (APAP) produces renal necrosis restricted to the straight segment of the proximal tubule in Fischer 344 (F344) rats. On the other hand, Sprague-Dawley (SD) rats are extremely resistant to the nephrotoxic effects of APAP. Such strain differences may be due to different susceptibilities to the nephrotoxic metabolite, p-aminophenol (PAP). PAP administration in both strains of rats resulted in a renal lesion indistinguishable from the APAP-induced renal lesion in F344 rats. The PAP-induced renal lesions in F344 rats, however, were generally more severe than those in SD rats. PAP-induced renal functional changes (elevation in blood urea nitrogen and reduction in the accumulation of p-aminohippurate by renal cortical slices) correlated with strain-dependent histopathological changes. Analysis of urinary metabolites over a 24-hr period following PAP administration (200 and 400 mg/kg) indicated that more PAP was excreted as APAP in SD than in F344 rats. Covalent binding of PAP to renal microsomes in vitro was much greater in F344 rats than in SD rats at substrate concentrations less than 5 mM. These results suggest that strain differences in PAP-induced nephrotoxicity may be related to differences in the intrarenal activation of PAP. Furthermore, strain differences in APAP-induced nephrotoxicity may be related to strain differences in the activation of the nephrotoxic metabolite, PAP.

Acetaminophen↗

PubMed1983

Effects of aminoglycosides on glomerular permeability, tubular reabsorption, and intracellular catabolism of the cationic low-molecular-weight protein lysozyme.

Gentamicin and other aminoglycoside antibiotics in high doses may produce proteinuria and other signs of nephrotoxicity. Proteinuria may result from general renal damage or may reflect alterations in specific steps in the renal handling of proteins. To distinguish between these two possibilities, experiments were designed to quantify the effects of nephrotoxic doses of several aminoglycosides on the renal handling of proteins in the isolated perfused rat kidney with the cationic low-molecular-weight protein lysozyme as a representative protein. Each aminoglycoside was administered ip to male Wistar rats (30 mg/kg/day) for 7 days. Lysozyme and 125I-lysozyme were added to the perfusate to achieve a lysozyme perfusate concentration of about 100 mg/liter. Clearances of inulin and lysozyme, release of tyrosine and trichloroacetic acid-soluble radioactive metabolites into the perfusate, and the glomerular sieving coefficient of lysozyme were determined. Scanning and transmission electron microscopy indicated that gentamicin and tobramycin decreased the number and diameter of the endothelial fenestrae of the glomerular capillaries. Concurrently, gentamicin and tobramycin decreased the glomerular sieving coefficient of lysozyme from 0.8 to 0.6 and 0.5, respectively. Netilmicin did not affect the percentage reabsorption of lysozyme whereas gentamicin and tobramycin decreased lysozyme reabsorption from 71.7 to 35.4 and 34.4% of the filtered load, respectively. Lysozyme degradation, estimated by the release of tyrosine into the perfusate during a 150-min perfusion period, was decreased from a control value of 12 mumol/liter to 4.43 and 4.65 mumol/liter in kidneys from rats treated with gentamicin and tobramycin, respectively. This study demonstrates that polycationic aminoglycosides may affect several processes involved in renal handling of lysozyme including glomerular permeability, tubular reabsorption, and intracellular proteolytic degradation.

Absorption↗

PubMed1983

Perinatal hexachlorobenzene toxicity in the mink.

Adult female standard dark mink were exposed to hexachlorobenzene (HCB) at concentrations of 0, 1, and 5 ppm in the feed and bred with males on the same treatments. Female offspring were allowed to mature to 16-17 weeks and killed. At 16-17 weeks of age, HCB had no effect on body weights or liver weights. Hepatic cytochrome P-450 and ethoxyresorufin-O-deethylase were significantly increased 2.0- and 1.5-fold, respectively, in the 5-ppm treatment group. Electron microscopy failed to reveal proliferation of the smooth endoplasmic reticulum. No hepatic damage was observed. No changes in in vitro renal function, measured as accumulation of para-aminohippurate and tetraethylammonium by renal cortical slices, were detected in any treatment group. Histological examination of renal slices did not reveal any alterations in morphology. Fat was the predominate site of HCB disposition; samples from the 5-ppm treatment group contained 626.10 +/- 12.01 ng HCB/g tissue. Whereas perinatal HCB administration has profound effects on the survival of offspring born to exposed mink, only induction of hepatic mixed-function oxidases was observed in the surviving kits without any observable frank hepatotoxicity.

Adipose Tissue↗

PubMed1983

The effect of prenatal methylmercury administration on postnatal renal functional development.

In utero exposure of rats to methylmercury has been reported to produce degenerative and hyperplastic changes in renal proximal and distal tubules, although no assessment of postnatal renal functional capacity was made. CH3HgCl was administered ip to Sprague-Dawley rats on Day 8 of gestation at 4 or 6 mg Hg/kg or on Days 8, 10, and 12 at 4 mg Hg/kg (3 x 4 mg Hg/kg). These doses produced no overt toxicological effects nor had any effect on litter size, body weight, or kidney weight to body weight ratios. The concentration of mercury in kidneys, liver, and brain at 1 and 7 days postpartum was dose-related but was not detectable at 42 days. In vitro renal function was assessed in renal cortical slices from rats at 1, 7, and 42 days postpartum by determining the ability to accumulate organic ions and to generate glucose. Additionally, parameters of in vivo renal function were determined in normopenic, hydropenic (5 pressor units/kg ADH, sc, 18 hr water deprived), and in volume-loaded male rats at 42 days postpartum. At 42 days postpartum in the 3 x 4 mg Hg/kg treatment group, p-aminohippurate accumulation was depressed slightly as was the ability to eliminate Na+ and water in volume-loaded rats. These data suggest that postnatal renal physiological sequelae to prenatal administration of methylmercury may be less than predicted from histological studies.

Animals↗