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Biomedical subjects

J B Hook

Publications and source records attributed to J B Hook.

At least 163 records · Page 9Linked to original sources
PubMed1978

Selective modification of the renal and the hepatic toxicities of chloroform by induction of drug-metabolizing enzyme systems in kidney and liver.

Renal and hepatic microsomal enzyme activities were measured in ICR male mice treated with phenobarbital (PB), 3-methylcholanthrene (3MC), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or polychlorinated biphenyls (PCB). The effect of these agents on subsequently administered single doses of chloroform (CHCI3) were also determined. 3MC, TCDD and PCB increased renal as well as hepatic microsomal enzyme activities. PB increased hepatic but not renal microsomal enzyme activities. The hepatotoxicity of CHCI3 was increased by pretreatment with PB but decreased by pretreatment with TCDD. 3MC and PCB were without effect on CHCI3-induced liver damage. Pretreatment with 3MC, TCDD or PCB reduced the renal toxicity of CHCI3, but PB had no effect on CHCI3-induced kidney damage. Since at least one product of enzymatic metabolism of CHCI3 is believed to be a toxic, reactive intermediate the differential effects of inducers of microsomal drug-metabolizing enzyme activities on the renal and hepatic toxicities of CHCI3 strongly suggest that the CHCI3 metabolite(s) ultimately responsible for renal and hepatic damage are not generated at a common site. That is the metabolite responsible for hepatic is probably generated in the liver and the metabolite responsible for renal damage is probably generated in the kidney.

Animals↗
PubMed1978

Renal tubular transport of saccharin.

These experiments were designed to examine the mechanisms involved in the renal excretion of the non-nutritive sweetener, saccharin. Renal transport of saccharin in female rats was quantitatively evaluated using renal cortical slices in vitro and renal clearances in vivo. Renal cortical slices actively accumulated saccharin. Accumulation was oxygen dependent, saturable and reduced in the presence of metabolic inhibitors (2,4-dinitrophenol and sodium azide) and other organic anions 1p-aminohippurate (PAH) and probenecid]. Furthermore, addition of acetate or lactate to the medium stimulated saccharin uptake whereas reducing potassium concentration in the medium significantly decreased saccharin accumulation. Addition of saccharin to medium containing PAH and N-methylnicotinamide produced a dose-related depression of PAH accumulation. Although N-methylnicotinamide accumulation also was reduced, the depression was not dose-related. The saccharin/inulin clearance ratio of 3.76 indicates that saccharin, like PAH, undergoes tubular secretion. These findings suggest that the primary route of renal elimination of saccharin is active tubular secretion. It is also suggested that saccharin and PAH may share a common transport system.

Animals↗
PubMed1978

Effect of tolmetin on renal function and prostaglandin metabolism.

The effect of tolmetin on prostaglandin synthesis by minces of rat renal medulla and on prostaglandin cyclooxygenase of rabbit renal medulla was determined in vitro. The effect of tolmetin was compared to the effects of indomethacin and ibuprofen. Pretreatment of rats in vivo with tolmetin, indmethacin or ibuprofen reduced prostaglandin synthesis by minces of renal medulla. Incubation of medullary tissue in medium containing tolmetin or indomethacin also decreased prostaglandin production. Both drugs reduced O2 consumption by prostaglandin cyclooxygenase from rabbit renal medulla. In addition, the effect of tolmetin, indomethacin and ibuprofen on renal blood flow and the intrarenal distribution of renal blood flow was measured in anesthetized dogs. Tolmetin and ibuprofen resemble indomethacin in reducing renal blood flow and in shifting the distribution of renal cortical flow from the inner cortex toward the outer cortex. It is concluded that tolmetin is an effective inhibitor of prostaglandin synthesis and affects renal function in a fashion similar to other prostaglandin synthesis inhibitors.

Animals↗
PubMed1978

Chemical induction of p-aminohippuric acid transport in renal cortical slices from adult and immature rabbits.

Fourteen-day-old and adult rabbits received procaine penicillin G (PEN), 450,000 U/kg s.c., every 12 hours for a total of four doses or phenobarbital-Na (PHB), 40 mg/kg i.p., once daily for 3 days, or 3-methylcholanthrene (3MC), to 20 mg/kg i.p., once daily for 3 days. Twenty-four hours after the final treatment the animals were killed and the kidneys were removed for analysis of enzymatic activities and p-aminohippuric acid (PAH) transport capability. PEN, PHB and 3MC had no effect on PAH transport in slices from adult rabbits but significantly increased PAH transport in slices from 14-day-old rabbits. Aryl hydrocarbon hydroxylase activity was enhanced in both adult and 2-week rabbit kidneys by 3MC while biphenyl-4-hydroxylase activity was enhanced in 2-week and adult rabbit kidneys by PHB. Epoxide hydratase was unaffected by all three treatments. 3MC increased gluthione-S-aryltransferase (ligandin) activity in 2-week but not adult kidneys. Induction of PAH transport in 14-day-old rabbits does not appear to be related to stimulation of microsomal enzymes or glutathione-S-aryltransferase activity in the kidney. Although they are not considered to be substrates for renal organic anion transport, PHB and 3MC resemble PEN in their ability to induce PAH transport in renal cortex of immature but not adult rabbits.

Aging↗
PubMed1978

Alteration of renal cortical palmitate utilization and p-aminohippurate (PAH) accumulation after penicillin treatment of neonatal rabbits.

The renal organic anion transport system has been linked to the selective extraction of nonesterified fatty acids (NEFA) from arterial blood. Consequently, p-aminohippurate (PAH) and palmitate may compete for a common intracellular binding site or may be handled by a common enzymatic pathway. The purpose of this study was to identify sites of interaction by correlating alterations in PAH accumulation and palmitate metabolism after selective stimulation of the PAH transport system. Penicillin treatment of immature rabbits increased PAH accumulation by suspensions of proximal tubules prepared nonenzymatically) and altered distribation of incorporated palmitate[14C] within tubule lipid classes. Penicillin increased palmitate[14C] esterified to triglycerides and decreased 14C recovered as NEFA. Administration of iodipamide had no effect on PAH accumulation and did not alter palmitate utilization. Penicillin treatment of mature rabbits did not alter either tubule PAH accumulation or palmitate esterification. These results suggested that palmitate and PAH share a common intracellular binding site and that penicillin enhanced PAH accumulation by removing endogenous inhibitors (NEFA).

Aging↗
PubMed1978

The effect of indoprofen on phenylquinone-writhing and prostaglandin synthesis.

The ability of indoprofen or sodium indoprofen to inhibit phenylquinone-writhing and renal prostaglandin synthesis was determined in mice following a single oral dose of either drug. Male mice (4/group) were treated with 1.5 mg/kg indoprofen or sodium indoprofen. Inhibition of phenylquinone-writhing was determined at 2, 4, 8, 16 and 32 hr post treatment. Animals were sacrificed and blood collected for determination of plasma indoprofen concentration. Kidneys were removed and prepared for determination of renal prostaglandin synthesis by an in vitro technique. Phenylquinone-writhing was significantly depressed by both preparations at 2 and 4 hr post treatment. Sodium indoprofen also significantly depressed writhing at 8 hr post treatment. Renal prostaglandin synthesis, like phenylquinone-writhing, was significantly depressed at 2 and 4 hr after drug treatment. Plasma indoprofen concentration was correlated with both inhibition of phenylquinone-wrighing and inhibition of renal prostaglandin synthesis. When writhes were plotted versus prostaglandin synthesis, a positive correlation was observed suggesting a temporal relationship between inhibition of phenylquinone-writhing and inhibition of renal prostaglandin synthesis.

Analgesics↗
PubMed1977

Development of mechanisms for drug excretion.

Renal excretion of many drugs is less in the newborn than what would be predicted in terms of body weight. This is due, in part, to low renal blood flow and glomerular filtration rate during the immediate newborn period. In the first weeks to months of postnatal life, renal vascular resistance decreases and blood flow increases. Subsequently, the glomerular filtration rate increases. During this time, drug elimination may also be affected by qualitative and quantitative differences in binding of drugs to plasma proteins. In addition, drug elimination may be prolonged due to an immature ability in the newborn to transport or metabolize drugs in the kidney. Recent evidence demonstrated that drugs administered pre- or postnatally may alter the rate of renal excretion of drugs in the newborn. Such effects are of great concern to the clinician and underscore the importance of monitoring drug blood levels in these patients. From another perspective, the ability to stimulate drug excretion has been used as a tool to study basic renal physiology. Quantitative patterns of development coupled with the use of substrate stimulation provided evidence for at least three transport systems for organic anions in the proximal tubule. Similar technics provided preliminary data linking drug metabolism and organic anion transport in the proximal tubule, whereas an obligatory, rate-limiting role for ligandin in anion transport could not be established.

Adult↗
PubMed1977

Inhibition of prostaglandin synthesis by indoprofen.

Many non-steroidal anti-inflammatory, analgesic drugs appear to produce their effects by inhibiting prostaglandin synthesis. These investigations were undertaken to determine whether a new anti-inflammatory compound, indoprofen, inhibited prostaglandin synthesis in vitro when present in incubation medium or following systemic administration. The results indicated that indoprofen effectively inhibited prostaglandin synthesis in kidney and uterus. Indoprofen was equally effective as indomethacin and aspirin in inhibiting prostaglandin synthesis. The relative potency of the drug was intermediate between indomethacin and aspirin.

Animals↗
PubMed1977

Glutathione S-transferases: an evaluation of their role in renal organic anion transport.

Organic anion transport capacity measured as accumulation of p-aminohippurate by renal cortical slices was less in kidneys from newborn rats and rabbits than adults and increased with age. Glutathione (GSH) S-aryltransferase activity in 100,000 X g supernatant of renal homogenates, an estimate of GSH-S-transferase concentration in the tissue, was also less in newborn of both species. Enzyme activity increased to adult values by 1 week of age in rats, prior to maturation of transport capacity. Enzyme activity in rabbit kidney was not different at 1 day and 2 weeks but was increased by 4 weeks coincident with transport maturation. In rats, 25 mg/kg of 3-methylcholanthrene administered once a day for 3 days significantly increased enzyme activity but had no effect on transport capacity. Chronic ammonium chloride acidosis increased enzyme activity 8-fold but decreased transport capacity. Forty-eight hours after unilateral nephrectomy in rats transport capacity was significantly increased with little effect on enzyme activity. L-Methionine-SR-sulfoximine (1.85 mmol/kg) significantly reduced glutathione concentration in renal cortex but had no effect on transport capacity. Organic anion transport was greater in male than in in female mice yet there was no difference in enzyme activity between sexes. 3-Methylcholanthrene (10,20, 30 and 40 mg/kg) administered to 2-week-old rabbits twice daily for 3 days increased transport in a dose-dependent manner. GSH S-transferase activity was also increased. Penicillin (90,000 I.U. twice daily for 2 days) similarly increased transport but had no stimulating effect on enzyme activity. The apparent lack of correlation between transport capacity and GSH S-transferase in several instances suggests that GSH S-transferase concentration is probably not the rate-limiting step in renal organic anion transport.

Aging↗
PubMed1976

Effect of substrate pretreatment on renal organic ion transport in the adult rat.

The ability of renal cortical slices to accumulate PAH and NMN was not significantly affected by pretreatment of adult rats with large doses of PAH. Pretreatment of adult rats with THAM significantly increased PAH accumulation but had no effect on NMN. Inulin and PAH clearance and filtration fraction were significantly decreased by PAH pretreatment but unaffected by THAM pretreatment. The effects of pretreatment on transport are probably due to non-specific toxicity.

Aminohippuric Acids↗