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J J Hjelle

Publications and source records attributed to J J Hjelle.

At least 19 recordsLinked to original sources
PubMed1992

Plasma concentrations and pharmacokinetics of phenylalanine in rats and mice administered aspartame.

Aspartame (L-aspartyl-L-phenylalanine methyl ester) is an esterified, dipeptide sweetener that is rapidly and completely metabolized in the gastrointestinal tract to phenylalanine, aspartic acid and methanol. The pharmacokinetics of phenylalanine (PHE) and tyrosine (TYR) were examined following the administration of oral doses of aspartame (APM) to fasted male Sprague-Dawley rats (0, 50, 100, 200, 500 and 1,000 mg/kg) and CD-1 mice (0, 100, 200, 500, 1,000 and 2,000 mg/kg). Peak plasma PHE/large neutral amino acid (LNAA) ratios were calculated. Maximal plasma PHE and TYR concentrations were observed within 1 h after dosing and returned to baseline within 4-8 h in both species regardless of the dose of APM. Mean PHE Cmaxs ranged from 73.6 to 1,161 nmol/ml in the rat, and from 78.6 to 1,967 nmol/ml in the mouse. TYR Cmaxs ranged from 91.6 to 502 nmol/ml and from 89.2 to 792 nmol/ml in the rat and mouse, respectively. AUCs and Cmaxs were linear with dose in both species. Peak plasma PHE/LNAA ratios ranged from 0.112 to 1.117 in rats and from 0.121 to 1.769 in mice. Comparison of these ratios with those observed previously in humans indicates that rodents require a 2-6 times higher dose of APM than humans to produce similar increases in plasma PHE/LNAA ratios.

Administration, Oral↗
PubMed1989

Absence of developmental effects in CF-1 mice exposed to aspartame in utero.

Aspartame (L-aspartyl-L-phenylalanine methyl ester) is a widely used high potency dipeptide sweetener. Developmental toxicology studies have been performed in several species documenting no effects of high doses of aspartame. Recently, a study by Mahalik and Gautieri [1984) Res. Commun. Psychol. Psychiatry Behav. 9, 385-403) reported a delay in the achievement age for the visual placing response in mice pups after maternal administration of high dosages of aspartame during late gestation. In the present study developmental parameters were determined in offspring of CF-1 mice after maternal administration of aspartame at 500, 1000, 2000, and 4000 mg/kg body wt by oral gavage. Aspartame was administered on Days 15 through 18 of gestation. Maternal body weight, food consumption, gestation length, reproductive indices, and litter size were not affected by aspartame treatment. In the pups, body weights, negative geotaxis, and surface and midair righting reflexes were not altered by treatment. There was no delay in the development of the visual placing response regardless of the method employed for assessment (grid or rope) or the manner by which the data were analyzed. There were also no changes in time of eye opening, reflex pupil closure, and ophthalmoscopic examination in the offspring. Thus, neither physical nor functional development was altered in mice after in utero exposure to extremely large dosages of aspartame. More specifically, in utero exposure to aspartame did not affect the development of the visual system in mice.

Animals↗
PubMed1987

Comparison of the effects of ethanol and 4-methylpyrazole on the pharmacokinetics and toxicity of ethylene glycol in the dog.

The purpose of this investigation was to compare the effects of ethanol and 4-methylpyrazole (4MP) on the toxicity and pharmacokinetics of ethylene glycol (EG) in the dog. All dogs received 173 mmol/kg EG, p.o. Dogs were randomly assigned to 3 groups: EG-treated only, EG + ethanol (19.3 mmol/kg, i.v. 3, 7, 14 and 24 h after EG) and EG + 4MP (0.24 mmol/kg, i.v. 3 h after EG, 0.18 mmol/kg at 24 h and 0.06 mmol/kg at 36 h). EG produced a rapid onset of metabolic acidosis (within 3 h) and acute oliguric renal failure (after 48 h), whereas administration of ethanol or 4MP greatly attenuated acidosis and prevented renal toxicity. The administration of ethanol, however, severely increased the central nervous system (CNS) depression that existed after ingestion of EG. The half-life of FG in serum was 10.8 +/- 0.7 h in the EG-only treatment group, 6.8 +/- 0.7 (P less than 0.05) in the EG + ethanol group and 9.8 +/- 0.9 h in the EG + 4MP group. Approx. 10% and 48% of the dose of EG was excreted unchanged in the urine at the 0-3 and 3-72 h periods, respectively. Treatment with 4MP increased the amount of EG excreted in the urine (71% from 3-72 h), whereas ethanol did not (51%). However, both ethanol and 4MP increased the rate constant of EG excretion into urine approx. 70%. These data demonstrate the utility of 4MP over ethanol for the treatment of EG-induced toxicity in dogs and indicate that ethanol and 4MP cause an increase in the rate constant of EG excretion in the urine and not a prolongation in EG half-life.

Animals↗
PubMed1987

Diphenylthiazole-induced changes in renal ultrastructure and enzymology: toxicologic mechanisms in polycystic kidney disease?

The mechanism by which various chemicals induce renal cystic disease is unknown. To examine the early events in cystogenesis the ultrastructure and biochemistry of liver and kidney were analyzed after the administration of a chemical that induces renal cyst formation. Special emphasis was placed on examining potential mechanisms that would account for the observed loss of extracellular proteoglycans. Renal cystic disease was chemically induced in rats by feeding 2-amino-4,5-diphenylthiazole (DPT) for up to 4 weeks. After 4 days of feeding, DPT had induced a 4-fold increase in total urine output relative to diet-restricted control groups. Both groups maintained, but did not gain, weight during the feeding schedule. Cyst formation was localized to the medullary collecting tubules. Relative to diet-restricted controls, rats fed DPT exhibited diminished renal and hepatic catalase activity, but elevated activity for UDP-glucuronosyltransferase. Medulla showed an increase in the specific activities of the enzymes galactosyltransferase and sulfatase B. These enzymological findings correlated with ultrastructural observations of a loss of peroxisomes, proliferation of endoplasmic reticulum and enlargement of the golgi apparatus. Serum and urinary levels of inorganic sulfate were significantly increased in DPT-fed rats relative to controls. Tissue levels of UDP-glucuronic acid and adenosine 3'-phosphate 5'-phosphosulfate were not depressed by DPT feeding. Thus, DPT-induced cyst formation and loss of staining for glycosaminoglycans does not involve gross depletions of UDP-glucuronic acid and adenosine 3'-phosphate 5'-phosphosulfate, mutual cosubstrates for Phase II drug conjugation reactions and glycosaminoglycan synthesis.

Animals↗
PubMed1986

Effects of butylated hydroxyanisole on acetaminophen hepatotoxicity and glucuronidation in vivo.

The present study examined the effects of butylated hydroxyanisole (BHA) on acetaminophen-induced hepatotoxicity and metabolism in vivo with emphasis on possible changes in the glucuronidation pathway. Female Swiss-Webster mice received BHA in the diet (1% w/w) for 12 days (600 to 800 mg/kg/day). BHA prevented acetaminophen hepatotoxicity (600 mg/kg, ip), based on serum alanine and aspartate aminotransferase activities and histopathological examination. The rate of elimination of acetaminophen from blood was 10-fold higher in BHA-fed mice (clearance, 49 ml/min/kg) than in controls (4.4 ml/min/kg). In general, the urinary metabolite excretion patterns in control and BHA-treated mice were the same. However, the rates of acetaminophen conjugation via the sulfation, glucuronidation, and mercapturic acid pathways were enhanced with the rate of glucuronide formation, the major biotransformation pathway of acetaminophen, increased sevenfold in BHA-treated mice (0.041 min-1) compared to controls (0.006 min-1). BHA increased hepatic UDP-glucuronosyltransferase activity twofold, as well as hepatic UDP-glucuronic acid concentrations. In addition, after acetaminophen administration, UDP-glucuronic acid in BHA-treated mice was depleted to a lesser extent and returned to control values more rapidly than in untreated animals. BHA had a similar but less pronounced effect on hepatic glutathione levels. The findings indicate that the rate of acetaminophen glucuronidation is increased in vivo during BHA feeding to mice. This effect appears to play a role in the enhanced excretion of acetaminophen as well as protection against acetaminophen-induced hepatotoxicity.

Acetaminophen↗
PubMed1986

Glucuronidation and sulfation in rabbit kidney.

Mammalian kidneys contain a heterogeneous population of cell types that perform a variety of diverse functions. The present study was undertaken to determine the relative intrarenal distribution of UDP-glucuronosyltransferase and sulfotransferase activities. Female rabbit kidneys were dissected, and homogenates of cortex, outer stripe of the medulla and proximal tubule segments were prepared. Proximal tubule segments, derived primarily from the S2 region of the tubule, were isolated using purely mechanical methods. UDP-Glucuronosyltransferase and sulfotransferase activities directed toward 1-naphthol were highest in proximal tubules (2.86 +/- 0.13 nmol and 133 +/- 13.1 pmol product formed/min/mg protein, respectively) compared to outer stripe (45% and 64% of proximal tubule activity, respectively) and cortex (61% and 45%, respectively). Detergent increased 1-naphthol glucuronidation in homogenates of cortex and medulla, but depressed activity in proximal tubules. Subcellular fractionation of proximal tubule cells by isopycnic and rate density centrifugation revealed that UDP-glucuronosyltransferase activity distributed with the denser components of the endoplasmic reticulum and/or Golgi. Moreover, although the majority of sulfotransferase activity distributed as free (cytosolic) protein, sulfotransferase activity was also observed in fractions containing denser components of the endoplasmic reticulum and Golgi. Proximal tubule segments also exhibited the highest specific activity of UDP-glucose dehydrogenase, the enzyme involved in UDP-glucuronic acid synthesis (1.5-fold higher in tubules than in other regions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Hepatic UDP-glucuronic acid regulation during acetaminophen biotransformation in rats.

Acetaminophen (AA) glucuronidation is capacity limited in several species after administration of high doses and previous data indicate that this phenomenon is due probably to a decrease in the concentration of the reaction cosubstrate UDP-glucuronic acid in liver. The rate-limiting determinant in UDP-glucuronic acid synthesis during AA glucuronidation is not known. The objective of the present study was to determine whether UDP-glucuronic acid synthesis during AA biotransformation is restricted by the supply of UDP-glucose or is limited by UDP-glucose dehydrogenase activity. Adult male Sprague-Dawley rats were injected with 600 mg/kg i.p of AA and liver was obtained 30, 60, 120 and 240 min later for quantitation of UDP-glucose, glycogen and UDP-glucuronic acid. AA was found to decrease markedly UDP-glucuronic acid concentration in liver 30, 60 and 120 min after injection (28, 52 and 58% of control values, respectively). In contrast, hepatic UDP-glucose levels were not altered after 30 min, but were decreased to 55 and 68% of control values 60 and 120 min after AA administration. Glycogen concentrations were decreased at the 30-min time interval only (78% of control). Therefore, maximal depletion of UDP-glucuronic acid occurred when UDP-glucose levels were not affected. UDP-glucose dehydrogenase is subject to product inhibition by NADH and UDP-glucuronic acid and it is possible that NADH accumulates during rapid utilization of UDP-glucuronic acid. Consequently, the effects of AA on cytosolic NADH/NAD ratios in liver were examined by determining the lactate/pyruvate ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed1986

Comparison of the effects of sodium sulfate and N-acetylcysteine on the hepatotoxicity of acetaminophen in mice.

N-acetylcysteine (NAC) has been proposed to decrease the toxicity of acetaminophen (AA) via two mechanisms: by increasing cysteine availability for hepatic glutathione biosynthesis and by increasing inorganic sulfate levels, which would increase AA sulfation and elimination. Because administration of sodium sulfate also reportedly decreases AA-induced toxicity, we have investigated the role of inorganic sulfate in the antidotal properties of NAC. Simultaneous administration of NAC (4 mmol/kg) and AA (2.5 and 4 mmol/kg) to male mice prevented AA-induced lethality and hepatotoxicity whereas sodium sulfate (4 mmol/kg) did not. Neither NAC nor sodium sulfate produced significant changes in the half-life (44 min) or clearance (9.0 ml/min/kg) of AA (4.0 mmol/kg) from blood nor were the amounts of AA-sulfate, AA-cysteine or AA-mercapturate excreted in urine altered. Injection of either sodium sulfate or NAC increased serum sulfate concentration and prevented the depletion in serum sulfate produced by AA. Hepatic adenosine 3'-phosphate 5'-phosphosulfate concentrations were decreased 15 and 30 min after AA and injection of either sodium sulfate or NAC lessened this effect. The concentration of glutathione in liver was decreased markedly after AA. NAC attenuated this effect but sodium sulfate did not. Sodium sulfate did not decrease covalent binding of tritium derived from [3H]AA to liver protein whereas NAC decreased binding by 25%. These findings show that administration of sodium sulfate increases serum sulfate concentration and hepatic adenosine 3'-phosphate 5'-phosphosulfate levels but does not protect against acetaminophen-induced hepatotoxicity in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed1986

Effects of cysteine pro-drugs on acetaminophen-induced hepatotoxicity.

The effects of three cysteine pro-drugs on the hepatotoxicity and biotransformation of acetaminophen were examined to evaluate the factors responsible for antidotal effectiveness. N-Acetyl-L-cysteine, L-2-oxothiazolidine-4-carboxylate or the L- or D-isomers of 2-methylthiazolidine-4-carboxylate were administered to male mice immediately after a hepatotoxic dosage of acetaminophen (5.0 mmol/kg). In general the antidotal efficacies and potencies of the L-cysteine pro-drugs were similar; 5.0 mmol/kg prevented hepatotoxicity whereas moderate and no protection were observed after 1.65 and 0.55 mmol/kg, respectively. In contrast, the D-isomer of 2-methylthiazolidine-4-carboxylate was ineffective at all dosages. Both L-2-oxothiazolidine-4-carboxylate and L-2-methylthiazolidine-4-carboxylate enhanced blood acetaminophen elimination (28-31% decrease in half-life) whereas N-acetyl-L-cysteine and D-2-methylthiazolidine-4-carboxylate did not. The L-cysteine pro-drugs increased the urinary excretion of the cysteine and mercapturic acid conjugates of acetaminophen (34-119%) but did not alter excretion of acetaminophen-glucuronide or acetaminophen-sulfate. The D-cysteine pro-drug did not affect the urinary excretion of the acetaminophen metabolites examined. Biochemical analyses of the phase II pathway co-substrates, i.e., UDP-glucuronic acid, adenosine 3'-phospho-5'-phosphosulfate and glutathione, were performed on liver samples from mice treated with pro-drugs and/or acetaminophen. The pro-drugs exhibited their greatest effect on hepatic glutathione concentrations. Treatment with L-cysteine pro-drugs decreased the extent of depletion and/or increased the rate of repletion of hepatic glutathione levels after acetaminophen administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed1985

Effects of butylated hydroxyanisole on hepatic glucuronidation capacity in mice.

The present study has examined biochemical mechanisms by which butylated hydroxyanisole (BHA) increases the glucuronidation of xenobiotics. Male and female Swiss Webster mice received BHA in the diet (1% w/w) for 10 days (600 to 800 mg/kg/day). Hepatic UDP-glucuronosyltransferase activities were increased toward specific substrates in native and detergent-activated microsomes. In general, BHA increased glucuronidation toward group 1 substrates (1-naphthol and 4-nitrophenol) 36 to 141% whereas no changes were found with a group 2 (chloramphenicol) or a group 3 substrate (digitoxigenin monodigitoxoside). Also, activities toward unclassified substrates (estrone, acetaminophen, and diethylstilbestrol) were increased (29 to 139%) by BHA. BHA treatment also increased hepatic UDP-glucuronic acid content (two- to threefold) by increasing UDP-glucose concentration (30 to 50%) and enhancing UDP-glucose dehydrogenase activity (300 to 400%). BHA had a more pronounced effect in female than male mice when data were expressed as activity or amount per liver because BHA treatment selectively increased the liver weight in female mice. In conclusion, BHA increases the capacity for glucuronidation in mice by elevating both UDP-glucuronosyltransferase activities and UDP-glucuronic acid concentration in liver.

Animals↗
PubMed1985

The effects of disopyramide phosphate on serum glucose and glucose counterregulation in the dog.

The effect of oral administration of the antiarrhythmic disopyramide phosphate (DPP) on serum glucose and glucose counterregulation was determined in beagle dogs. In addition, the hypoglycemic effect of DPP, a racemate, and its optical isomers was determined. DPP produced dose-dependent significant decreases in serum glucose concentrations. Maximum decreases in serum glucose concentrations were approximately 10% at 10 mg/kg, 15% at 30 mg/kg, and 30% at 100 mg/kg when DPP was given as single doses, and 30% at 100 mg/kg when DPP was given as three divided doses. In each case, serum glucose concentrations returned to control values within 24 to 30 hr. To evaluate the effect of DPP on glucose counterregulation the recovery from acute insulin-induced hypoglycemia was determined. No differences of any practical significance were observed between the insulin tolerance curves of control and 50-, and 100-mg/kg DPP groups. Thus, the overall glucose counterregulatory response following insulin challenge was unaffected by DPP. The hypoglycemic effects of DPP, (S)-(+)-DPP, and (R)-(-)-DPP were compared by examining the ratio of the areas under the curve of serum glucose concentration to serum drug concentration. The absolute ratio for the (S)-(+) isomer was significantly greater than that of the (R)-(-) isomer, indicating that the hypoglycemic effect of DPP is largely due to its (S)-(+) isomer.

Animals↗
PubMed1985

Role of sulfhydryls in the hepatotoxicity of organic and metallic compounds.

Endogenous sulfhydryl compounds serve a critical role in maintaining the function and viability of living systems. Glutathione (GSH) is the most abundant of these nonprotein thiols. During the past decade it has been demonstrated that sulfhydryls such as GSH also serve an important role in protecting vital nucleophilic sites in the liver from electrophilic attack by numerous classes of reactive chemicals. Organocompounds such as bromobenzene and acetaminophen which undergo microsomal metabolism yield reactive intermediates that are specifically inactivated by conjugation with sulfhydryls in the form of GSH. Thus, for organocompounds GSH is extremely important in protecting against toxic insults. More recently, other sulfhydryl compounds also have been found to serve a specific but as yet less defined role in protecting biological systems against chemically induced injury. Metals such as cadmium have a high affinity for sulfhydryls and the metal binding protein metallothionein binds cadmium with high affinity. The highly specific association of the metal with this sulfhydryl-enriched protein serves to effectively sequester the reactive cadmium ion. The central role of sulfhydryl equivalents in the detoxication of organo- and metallocompounds is similar; however, the mechanism by which this is achieved is fundamentally different.

Acetaminophen↗
PubMed1984

Transient induction of hepatic metallothionein following oral ethanol administration.

Chronic ethanol ingestion has been associated with alterations of zinc homeostasis. Various treatments that alter zinc disposition induce hepatic metallothionein (MT). Therefore, this study was performed to determine the effect of acute ethanol exposure on hepatic MT levels. Adult male CF-1 mice were administered ethanol intragastrically and their hepatic MT was quantified at various times thereafter by the Cd-radioassay method. Ethanol (5 g/kg, ig) produced significant increases in hepatic MT as early as 4 hr after dosing. Maximal hepatic MT concentrations (19-fold increase) were observed 24 hr after ethanol and returned to control concentrations by 48 hr. Hepatic MT levels were increased 24 hr after 5 or 7 g ethanol/kg but were not altered by 1, 2, or 3 g/kg. Elevations in pancreatic MT, but not in renal or intestinal MT, also occurred 24 hr after ethanol (5 g/kg). Actinomycin D (1.25 mg/kg, ip) prevented the increase in hepatic MT produced by ethanol, whereas inhibition of ethanol oxidation by pyrazole (150 mg/kg, ip) did not prevent the induction of hepatic MT. Gel filtration chromatography and uv spectral analysis confirmed the presence of MT in the livers of ethanol-treated mice. These data show that acute ethanol administration produces a marked elevation of hepatic MT that is transient.

Administration, Oral↗
PubMed1984

Glucuronidation and biliary excretion of acetaminophen in rats.

Dose-dependent acetaminophen pharmacokinetics is thought to be due to saturation of sulfation and glucuronidation, although its glucuronidation has not been thoroughly examined. Because many drug-glucuronides are extensively excreted into bile, the excretion of acetaminophen metabolites in bile was examined in urethane-anesthetized rats which received 37.5, 75, 150, 300 or 600 mg/kg of acetaminophen i.v. Disappearance of acetaminophen from plasma exhibited clear dose-dependency as determined by prolongation of T 1/2 and decreases in total body clearance at 150 mg/kg or higher. Biliary excretion of the various metabolites of acetaminophen increased from 20 to 49% as the dosage was increased from 37.5 to 600 mg/kg. The glucuronide conjugate was the major form of acetaminophen in bile at all dosages. Biliary excretion of the glucuronide conjugate increased from 10.5 to 40.2% of the recovered dose as the amount administered was increased to 600 mg/kg, whereas urinary excretion of the glucuronide conjugate remained relatively constant at approximately 20% of that recovered. Although the fraction of acetaminophen excreted as the glucuronide conjugate increased to over 70% of that recovered at the highest dose, a significant decline in the rate constant for glucuronide formation was noted at 300 mg/kg and higher. Likewise, the rate for glutathione conjugation was also lower at 300 mg/kg, whereas the formation of the sulfate conjugate was decreased at lower dosages (75 mg/kg). The results of the present study show that glucuronidation is a high-capacity, high-dose saturable pathway of acetaminophen biotransformation whose product is preferentially eliminated in bile after high dosages.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed1983

Metabolism of malondialdehyde by rat liver aldehyde dehydrogenase.

Mammalian liver contains a group of pyridine nucleotide linked aldehyde dehydrogenases [E.C. 1.2.1.3] which are present in high specific activity and possess wide substrate specificities. Malondialdehyde (MDA), a difunctional three-carbon aldehyde thought to be toxic, is generated during membrane lipid peroxidation in hepatocytes. The role of aldehyde dehydrogenase (ALDH) in the metabolism of MDA was tested in vitro with subcellular fractions and semipurified cytosolic preparations from rat livers. The cytosolic fraction accounted for virtually all of the MDA (50 microM) metabolizing activity observed in the postnuclear supernatant fraction. The rate of MDA disappearance was relatively low in the mitochondrial fraction and was not detectable in reaction mixtures which contained microsomes. Rat liver cytosol contained two ALDHs with MDA metabolizing activity. These enzymes were separated by DEAE-cellulose ion exchange chromatography and had apparent Km values of 16 microM and 128 microM for malondialdehyde. Mitochondria contained an ALDH enzyme with lower affinity (Km of 7.3 mM with NAD+) for malondialdehyde. These data show that rat liver contains at least three ALDH enzymes which oxidize malondialdehyde.

Aldehyde Dehydrogenase↗
PubMed1983

Time course of the carbon tetrachloride-induced decrease in mitochondrial aldehyde dehydrogenase activity.

Hepatic microsomal enzymes like cytochrome P-450 and glucose 6-phosphatase are inhibited after exposure to CCl4 in vivo. Since comparatively less is known about the effects of CCl4 on nonmicrosomal enzymes, we investigated the rapidity by which CCl4 inhibits the low Km mitochondrial aldehyde dehydrogenase (ALDH) isozyme, an enzyme known to be inhibited 24 hr after CCl4 treatment. The activity of this ALDH isozyme was significantly lowered 6 and 12 hr after a single 1 ml/kg intragastric dose of CCl4. The mitochondrial low Km ALDH specific activities exhibited a similar pattern of destruction/inhibition to the documented target enzyme microsomal cytochrome P-450 in that lowest values were observed 6 hr after CCl4. These values were 44 and 37% of control for cytochrome P-450 content and the low Km ALDH activity, respectively. Alcohol dehydrogenase activity, expressed as activity per gram liver, was depressed 12 hr after CCl4 dosing. Finally, the activity of the low Km cytosolic ALDH, the isozyme that metabolizes malondialdehyde at low concentrations, was not affected by CCl4 treatment. The CCl4-induced decline in the activity of the matrix ALDH isozyme occurs earlier than previously reported mitochondrial damage. The study of sensitive enzymes like the low Km ALDH may provide valuable information by which it may be possible to determine the relationship of the truly rapid biochemical effects of CCl4 such as microsomal lipid peroxidation with later effects on nonmicrosomal components.

Aldehyde Dehydrogenase↗