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Biomedical subjects

J B Hook

Publications and source records attributed to J B Hook.

At least 91 records · Page 5Linked to original sources
PubMed1982

Inhibition of mixed-function oxidase activities in vitro and in vivo: comparisons between kidney and liver.

The concentration-dependent abilities of SKF 525-A, metyrapone (MET), piperonyl butoxide (PB), allyl-isopropylacetamide (AIA) and alpha-naphthoflavone (7,8-benzoflavone; ANF) to inhibit the activities of p-chloro-N-methylaniline-N-demethylase (PCNMA) and aryl hydrocarbon hydroxylase (AHH) in vitro were determined in microsomal and postmitochondrial supernatant (PMS) fractions of homogenates prepared from kidneys and livers of rats and mice. Renal microsomal AHH was less sensitive to modulation by SKF 525-A, MET and ANF in vitro than was hepatic microsomal AHH, but renal and hepatic microsomal AHH were equisensitive to inhibition by PB. AIA did not inhibit AHH activities in vitro. Renal AHH and PCNMA activities in PMS fractions were less sensitive to inhibition by SKF 525-A, MET and PB than were hepatic AHH and PCNMA activities. The temporal characteristics of enzyme inhibition in vivo were studied in kidneys and livers removed 1, 2, 4 or 12 h after treatment of the animals with 75 mg kg-1 SKF 525-A or 600 mg kg-1 PB. The degree of inhibition of AHH and PCNMA activities produced by i.p. administration of the inhibitors were greater quantitatively in liver PMS than in kidney PMS, and the degree of inhibition of PCNMA activity in both organs was much less than that of AHH activity. The differences in sensitivity of renal and hepatic AHH and PCNMA activities to the inhibitors may have been due to organ-specific differences in the affinities of the inhibitors for interaction with the active site(s) on cytochrome P-450.

Animals↗
PubMed1982

Glucose intolerance following cis-platinum treatment in rats.

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.

Animals↗
PubMed1982

Effects of drug-metabolizing enzyme inducers on cephaloridine toxicity in Fischer 344 rats.

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.

Animals↗
PubMed1982

Synergistic toxicity of carbon tetrachloride and several aromatic organohalide compounds.

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.

Animals↗
PubMed1982

The effect of ethanol administration on renal and hepatic mixed-function oxidases in the Fischer 344 rat.

Administration of ethanol in the drinking water increases hepatic cytochrome P-450 content and xenobiotic metabolism. However, the effect on renal xenobiotic metabolism has not been investigated. Chronic consumption of ethanol (15% solution in the drinking water) increased hepatic cytochrome P-450 content as well as ethoxycoumarin-O-deethylase, aniline hydroxylase and benzphetamine-N-demethylase activities. No change in renal cytochrome P-450 was detected after chronic ethanol consumption whereas ethoxycoumarin-O-deethylase activity in renal microsomes was significantly increased.

Animals↗
PubMed1982

Cardiac and hepatic effects of pre- and postnatal exposure to polybrominated biphenyls in rats.

Body weight gain and hepatic concentrations of vitamin A were reduced in Sprague-Dawley rats by pre- and postnatal exposure to 100 ppm polybrominated biphenyls (PBBs). The ratio of liver weight to body weight, activity of hepatic delta-aminolevulinic acid (ALA) synthetase, and urinary excretion of uro- and coproporphyrins were increased by PBBs. Treatment with PBBs also increased the left atrial inotropic response to calcium. However, PBBs had no effect on development of the adrenergic neuronal transport system in heart, left atrial baselike peak tension, or inotropic response to ouabain. Thus PBBs retarded body weight gain and produced a variety of alterations in liver, but had little effect on cardiac contractile function.

5-Aminolevulinate Synthetase↗
PubMed1982

Nonrespiratory metabolic function and morphology of lung following exposure to polybrominated biphenyls in rats.

Exposure to polybrominated biphenyls (PBBs) resulted in increased activity of microsomal arylhydrocarbon hydroxylase and ethoxyresorufin-O-deethylase in rat lung. Clearance of 5-hydroxytryptamine (5-HT) and angiotensin 1 by perfused lungs was decreased by PBBs. However, PBBs had no effect on the activity of epoxide hydrolase, monoamine oxidase, or angiotensin-converting enzyme in lung. The only histopathologic change detected in lungs from PBB-treated rats was an increase in alveolar type II cell lamellar bodies. Selective accumulation of certain PBB congeners by lung was not observed in this investigation.

Animals↗
PubMed1982

Lack of effect of a purified diet on carbon tetrachloride or oxygen toxicity.

The study was designed to examine the effect of feeding a purified versus a cereal-based closed formula (control) diet on toxicity to carbon tetrachloride or oxygen. Twenty-eight-day-old male ICR mie were fed a purified or cereal-based closed formula diet for 14 or 84 days. After treatment with carbon tetrachloride or exposure to a 100% oxygen atmosphere, survival time and percentage survival were the same for mice fed either diet. In both dietary groups, carbon tetrachloride injection caused a similar decrease in hepatic nonprotein sulfhydryl compounds and glucose-6-phosphatase activity. It was concluded that, unlike previous findings with the herbicide paraquat, toxicity to carbon tetrachloride or oxygen is not increased by feeding a purified diet compared to a closed formula diet. The results provided further evidence to suggest that a free radical-lipid peroxidation process may not be the primary mechanism of the toxic effects of paraquat.

Animals↗
PubMed1982

Metabolism of acetaminophen by the isolated perfused kidney.

Acetaminophen (APAP) produces proximal tubular necrosis in the Fisher 344 rat. This lesion may result from the covalent binding of reactive intermediates of APAP to cellular macromolecules when glutathione (GSH) is sufficiently depleted. Experiments were designed to evaluate the ability of the kidney to convert APAP to reactive electrophilic metabolites capable of depleting renal GSH by quantifying GSH concentrations in isolated perfused kidneys perfused with APAP. Perfusion without APAP reduced (3 X 10(-5) -3 X 10(-5) M) to the perfusion medium further reduced renal GSH content. Treatment of rats with polybrominated biphenyls enhanced the ability of 3 X 10(-8) M APAP to deplete GSH. In contrast, treatment with piperonyl butoxide reduced the depletion of GSH produced by 3 X 10(-5) M APAP. At 3 X 10(-5) M APAP, the glucuronic acid, sulfate and the mercapturic acid conjugates were excreted by the isolate perfused kidneys. After treatment with polybrominated biphenyls, mercapturic acid excretion increased 4-fold, whereas the glucuronic acid and sulfate conjugate excretions were unaffected. These data suggest that the kidney can produce an electrophilic metabolite of APAP which can combine with and deplete renal GSH. An electrophilic metabolite of APAP produced by the kidney may initiate APAP induced renal necrosis.

Acetaminophen↗
PubMed1982

Zinc deficiency and the kidney. I. Effect on renal carbonic anhydrase activity.

Tissue zinc concentration and the activity of the zinc metalloenzyme, carbonic anhydrase, were quantified in whole blood and kidneys of weanling male Sprague-Dawley rats with diet-induced zinc deficiency. Zinc-deficient rats were fed ad libitum a commercially prepared diet containing less than 1 ppm zinc. Zinc-supplemented rats were ad libitum or pair-fed a control diet containing 60 ppm zinc. All animals were fed their respective diets for 3-6 weeks. Body and kidney growth were severely compromised after 3 and 6 weeks of feeding the zinc-deficient diet. Plasma and kidney zinc concentrations were significantly decreased in zinc-deficient animals after 6 weeks. While whole blood carbonic anhydrase activity of zinc-deficient rats was significantly greater than zinc-supplemented animals after 6 weeks, no differences in renal carbonic anhydrase activity were found between zinc-deficient animals and pair-fed controls. Results reported in this study suggest that zinc deficiency imposed at weaning in rats may be a contributing factor to retarded kidney maturation and alterations in blood carbonic anhydrase activity.

Animals↗
PubMed1982

Effects of vanadate on organic ion accumulation in rat renal cortical slices.

Sodium vanadate is a potent inhibitor of Na-K-adenosine triphosphatase. p-Aminohippurate (PAH) and tetraethylammonium accumulation in rat renal cortical slices was inhibited by vanadate in a dose-dependent manner at medium vanadate concentrations from 10(-6) to 10(-3) M. Inhibition was reversible at vanadate concentrations less than 1.5 x 10(-5) M. The slice content of vanadium (7.5-325 micrometer V/g wt. of tissue) was linearly related to medium vanadate concentrations ranging from 10(-5) to 10(-3) M. The ability of slices to generate glucose and ammonia was not impaired by medium vanadate concentrations up to 5 x 10(-4) M, a concentration that maximally inhibited organic ion accumulation. Increasing medium K+ concentrations potentiated vanadate inhibition of PAH accumulation which correlated with inhibition of sodium pump activity, as determined by 42K+ uptake. Intraperitoneal administration of vanadate (1 or 5 mg V/kg) to rats produced a profound diuresis and natriuresis during the 1st hr. Inhibition of PAH accumulation of renal slices from these rats was related to tissue vanadium concentrations. These data suggest that vanadate exerts its action on proximal tubule transport of PAH via inhibition of Na-K-adenosine triphosphatase.

Ammonia↗
PubMed1982

Alteration of toxicity to paraquat in mice fed a purified or cereal-based diet.

Toxicity to several compounds is affected by dietary changes that by themselves do not result in nutrient deficiency or toxicity. The herbicide paraquat was tested to determine whether feeding a cereal-based closed formula diet or a purified diet would affect the sensitivity of mice to paraquat. After an intraperitoneal injection of paraquat, 28-day-old male ICR mice, which had been fed a purified diet for periods of 3 to 84 days, had shorter survival times and lower 7-day percent survivals than mice fed a cereal-base closed formula diet. The median lethal dose of paraquat was significantly lower in mice fed the purified diet rather than the closed formula diet. Median effective time to death was also significantly shorter for male ICR mice fed the purified diet rather than the closed formula diet. Female ICR mice and male B6C3F1 mice fed the purified diet for 7 days were more susceptible to paraquat toxicity than similar mice fed the closed formula diet. Male C57BL/6J mice were more sensitive to the effects of paraquat regardless of the type of diet. Modifying the content of lipid, vitamin E, or selenium, or adding butylated hydroxytoluene to the purified diet did not prevent a decrease in 7-day percent survival and survival time compared to male ICR mice fed a closed formula diet. Male ICR mice fed the purified diet with egg-white protein had significantly longer survival times compared to mice fed the purified diet with casein. It is concluded that strictly defined diets must be used in the study of paraquat toxicity to control for any paraquat-diet interactions.

Animals↗
PubMed1982

Renal cortical accumulation of phenobarbital in rats and rabbits: lack of correlation with induction of renal microsomal monooxygenases.

Subchronic treatment with phenobarbital induces renal cortical microsomal monooxygenase activities (e.g., ethoxycoumarin O-deethylase, benzphetamine N-demethylase and arylhydrocarbon hydroxylase) and cytochrome P-450 content in rabbits but not in rats. The mechanism responsible for this species-specific difference in renal cortical enzyme induction remains unknown, but may be the result of differences in the renal cortical accumulation of phenobarbital by these two species. Rabbit kidneys may be capable of accumulating more phenobarbital than rat kidneys. In the present study, accumulation of phenobarbital by renal cortical slices and the disposition of phenobarbital in vivo were determined. Both rat and rabbit renal cortical accumulation of phenobarbital was partially energy-dependent and inhibited by SKF-525A. Renal cortical accumulation of phenobarbital in rats was also inhibited by piperonyl butoxide. Accumulation of phenobarbital in rabbit renal cortical slices was not greater than that in rat renal cortical slices. Furthermore, rabbit renal cortex did not accumulate more phenobarbital in vivo than rat renal cortex. These results suggest that the different enzyme inducing effects of phenobarbital in rat and rabbit kidneys is not due to quantitative differences in accumulation of phenobarbital in renal cortex.

Animals↗