Biomedical subjects

G Gadeholt

Publications and source records attributed to G Gadeholt.

50 records · Page 3Linked to original sources

PubMed1984

Ethanol and isoniazid induce a hepatic microsomal cytochrome P-450-dependent activity with similar properties towards substrate and inhibitors and different properties from those induced by classical inducers.

Male Wistar rats were pretreated with chronic ethanol ingestion (3 weeks), phenobarbital in the drinking water (1 week), beta naphtoflavone or trans-stilbene oxide (one daily i.p. injection for 3 days) or isoniazid (one daily i.p. injection for 7 days). All these treatments increased 4-nitroanisole O-demethylase activity above the control level. Kinetic studies indicated that ethanol and isoniazid induction gave low apparent K0.5 (less than 0.1 mM), trans-stilbene oxide and phenobarbital intermediate (0.1 mM less than K0.5 less than 0.5 mM) and beta naphtoflavone high K0.5 (greater than 0.5 mM) for the induced activities. Inhibition studies with 0.1 mM metyrapone, 0.1 mM imidazole or 5 mM 1,3-dioxolane provided further evidence that the induced activities had different properties. Differences were also observed in the subtypes of spectral type II interaction (IIa and IIb) with 0.1 mM imidazole or 0.1 mM metyrapone in the induced microsomes. The results indicate that demethylation of 4-nitroanisole is an effective reaction for distinguishing between three different types of cytochrome P-450 induction. The clinically important hepatotoxins ethanol and isoniazid appeared to induce the same type of cytochrome P-450 activity, and it is speculated that these toxins may predispose to hepatotoxicity by means of this common property.

Animals↗

PubMed1984

Tumor uptake of vincristine during close arterial vs systemic constant-rate infusion: experiments on sarcoma transplants in the rat kidney.

The uptake of vincristine (VCR) by normal tissues and by sarcomas transplanted to both kidneys in rats was studied at 10 min after constant rate infusion of 1 mg/kg body wt into one renal artery for 3, 10 and 30 min. Since the selectively infused kidney extracted only 2.5% of the total dose at the first renal passage, the present model provides a direct comparison between systemic and selective i.a. infusion of VCR in each animal. Tumor VCR uptake was 2.8 times higher and the corresponding blood VCR concentration time product about 4 times higher on the selectively infused side than on the contralateral side. Reduction of renal blood flow by clamping the selectively infused renal artery raised the local VCR blood concentration by another 10 times during 10 min infusion and further doubled the tumor uptake of VCR. Thus a 5-6 times higher VCR concentration in the tumor was achieved as compared to that obtainable by systemic administration of the same total dose. The results are compatible with a saturable mechanism of VCR uptake by renal tissue and tumors.

Animals↗

PubMed1984

Reduced synthesis of hepatic and plasma proteins in rats during diethyl ether anaesthesia.

The effect of diethyl ether anaesthesia on in vivo hepatic protein synthetic rates was tested in male Wistar rats. Protein synthesis was measured by an isotope technique after correction for measured levels of precursor specific radioactivity. It was shown that usual anaesthetic levels of diethyl ether reduced the rate of synthesis of liver proteins with 20% compared to a group receiving no anaesthesia. The synthesis/secretion of plasma proteins was much more inhibited, with approximately 70-80%, compared to animals either receiving no anaesthesia or pentobarbital. Monitoring of ether concentrations therefore seems necessary in experiments in which the hepatic capacity for protein synthesis/secretion is measured.

Anesthesia↗

PubMed1984

Ethanol-inducible cytochrome P-450 is more susceptible to in vitro carbon tetrachloride-mediated destruction than phenobarbital-inducible and beta-naphthoflavone-inducible cytochromes P-450.

Liver microsomes were incubated aerobically in vitro with NADPH and carbon tetrachloride in the presence of 1.5 mM EDTA. The resulting losses of haemoproteins and monooxygenase activities were evaluated after washing. Microsomes from ethanol-pretreated rats lost about 66% of their cytochrome P-450 measured as such, together with 94% of their ethoxycoumarin 0-deethylase activity. Microsomes from control and phenobarbital-pretreated rats lost between 30 and 35% of their cytochrome P-450 and between 65 and 50% of the ethoxycoumarin 0-deethylase activity. Microsomes from beta-naphtoflavone-pretreated rats lost about 10% of their cytochrome P-450 and 13% of their ethoxycoumarin 0-deethylase activity. The inhibition with tetrahydrofuran, metyrapone and alpha-naphtoflavone were also changed after incubation, suggesting selective destruction of isoenzymes with high affinity for tetrahydrofuran and selective sparing of others. Studies of 4-nitroanisole 0-demethylation indicated selective destruction of enzymes with high affinity for the 4-nitroanisole and sparing of enzymes with lower affinity. The properties that were destroyed after incubation with carbon tetrachloride were those that were elevated after chronic ethanol feeding. The destructive action of carbon tetrachloride in microsomes from ethanol-pretreated rats was found to be different from those of allyl alcohol and 2-isopropyl 4-pentenamide. The findings may have relevance to the enhancement of chronic ethanol feeding on the hepatotoxicty of carbon tetrachloride.

7-Alkoxycoumarin O-Dealkylase↗

PubMed1983

Binding of S-adenosylhomocysteine to various domains of the plasma membrane and to the endoplasmic reticulum from rat liver: relation between binding and phospholipid methyltransferase activity.

S-Adenosylhomocysteine (AdoHcy) binding to various membrane fractions of rat liver was determined at pH 7.4, using an oil centrifugation technique. The highest binding activity was found in the heavy microsomal (M-H) fraction enriched in endoplasmic reticulum, but high binding activity was also observed in the light microsomal fractions enriched in blood sinusoidal membranes (M-L fraction), and the heavy nuclear fraction (N-H fraction) containing the contiguous area. A substantial portion of AdoHcy binding activity in the M-L fraction may be ascribed to contamination of this fraction with endoplasmic reticulum, as indicated by the distribution of NADPH cytochrome c reductase activity. Binding activity was low in the light nuclear (N-L) fraction corresponding to the bile canaliculi. Phospholipid methyltransferase activity was determined in the same membrane fractions under similar conditions (pH 7.4), and in the absence and presence of added phospholipids. The distribution of the enzyme activity was dependent on the presence of exogenous phospholipids, and grossly similar to AdoHcy binding, the highest activities being observed in the M-H and the M-L fractions. The N-H fraction, rich in AdoHcy-binding activity, demonstrated, however, a very low phospholipid methyltransferase activity. It is concluded that AdoHcy-binding activity is not confined to the plasma membranes, and a major fraction of the binding activity resides on membranes derived from the endoplasmic reticulum. Also, the present results add to previous data suggesting that phospholipid methyltransferase does not totally account for the AdoHcy-binding sites on rat liver membranes.

Animals↗

PubMed1983

Acute ethanol intoxication decreases subsequent food intake and changes hepatic microsomal enzyme activities similarly to fasting.

The effect of intragastric ethanol, 7.8 g/kg, on the microsomal enzyme activities NADPH cytochrome c reductase, aminopyrine N-demethylase and aniline hydroxylase, were investigated in two sizes (150 g and 260 g) of mature male rats having free access to food and water for the 23 hours following ethanol administration. Controls received intragastric water and were given free access to food and water (fed controls) or only water (fasted controls). The ethanol group had a significantly lower food intake than the fed control group, and food intake in the large rats was more decreased by ethanol than that of the small rats, corresponding to slower recovery from intoxication. Ethanol and fasting increased aniline hydroxylation and decreased acetone enhancement of aniline hydroxylation to the same degree, whereas only fasting caused a significant decrease in aminopyrine N-demethylation. Some of the effects of acute ethanol intoxication on hepatic microsomal enzyme activities appear to be mediated via decreased food intake.

Alcoholic Intoxication↗

PubMed1983

Pharmacokinetics of naproxen after oral administration of two tablet formulations in healthy volunteers.

The pharmacokinetics of two naproxen tablet formulations were compared after oral administration. The 250-mg naproxen tablets, tablet I from AFI, Oslo, Norway, and tablet II Naprosyn, Astra-Syntex, were taken by 12 healthy volunteers in a randomized two-period crossover study. Plasma levels of naproxen were measured by a sensitive and specific HPLC method. The data were analyzed by means of two-way analysis of variance to test for significant differences between tablet formulation and differences between the first and second trial periods. Rapid absorption, with most Cmax values from 50-60 micrograms/ml reached within 1.5-3 h, was found for both tablet formulations. No significant difference was found in the rate and extent of absorption between the two formulations: the relative bioavailability of tablet I compared to tablet II was 1.05 +/- 0.21 (mean +/- SD). The naproxen concentration 2 h after ingestion and the Cmax were higher on the second occasion, regardless of preparation, suggesting that the subjects were clinically different on the two occasions.

Administration, Oral↗

PubMed1982

Effects of four restricted liquid diet regimens and one nonrestricted solid diet regimen on enzyme activities associated with hepatic drug metabolism.

Two different nutritionally adequate liquid diets containing either 18% protein, 47% carbohydrate and 35% lipid, or 18% protein, 12% carbohydrate and 70% lipid were given to rats once daily or in four divided doses for 3 weeks. The liquid diets decreased hepatic protein content and concentration and the activities of hepatic gamma-glutamyl transferase and NADPH cytochrome c reductase, compared to a zero time group fed chow and water. There were no important differences between the treatment groups. Aniline hydroxylase activity was also decreased by the liquid diets, but the high-lipid diet decreased the activity significantly less than the high-carbohydrate diet. Rats fed chow and water ad libitum for 3 weeks were less different from the zero time value than rats in any of the liquid diet groups. The effects of liquid diets may be important in alcohol research, where a high-carbohydrate liquid diet in restricted amounts is being widely used for feeding the control animals.

Animals↗

PubMed1981

Effects of diethyl ether anaesthesia on the pharmacokinetics of antipyrine and paracetamol in the rat.

The effects of two anaesthetic procedures: continuous administration of ether throughout the periods of drug infusion and blood sampling, and brief ether administration (5 min) before drug infusion were examined. Continuous ether reduced total anaesthesia had no effect on antipyrine kinetics, but caused a decrease in total clearance, k10 and V beta of paracetamol. The rates of distribution and redistribution of the drugs were unchanged by ether. The data suggest that ether interferes with the hepatic conjugation of paracetamol and may interfere with the hepatic oxidation of antipyrine and therefore should not be used as an anaesthetic when the kinetics of drugs with short elimination half-lives are studied. It may be used for drugs with longer half-lives.

Acetaminophen↗

PubMed1980

Hepatic microsomal drug metabolism, glutamyl transferase activity and in vivo antipyrine half-life in rats chronically fed an ethanol diet, a control diet and a chow diet.

The effects of chronic consumption of ethanol on several hepatic enzyme activities were investigated. Male Wistar rats (180 g) were divided in three groups, two of which were pair-fed ethanol or control liquid diets while the third group received chow and water ad libitum (untreated group). The following changes were observed after 1 and/or 6 weeks when expressed per 100 g b.w.: In the ethanol group, the amount of cytochrome P-450 increased as did the activities of aniline hydroxylase and glutamyl transferase. The in vivo half-life of antipyrine decreased. The activity of NADPH cytochrome c reductase in the ethanol group was different from the reference groups, but not changed compared to pre-experimental values. The activities of ethylmorphine N-demethylase and aryl hydrocarbon hydroxylase were decreased when expressed per gram of microsomal protein. In the control group, the activity of NADPH cytochrome c reductase declined and so did hepatic weight. The study gave support to a suspicion that feeding control diet may influence hepatic enzyme activities as well as relative liver weight. This influence may magnify ethanol effects on NADPH cytochrome c reducdase and relative liver weight when such effects are measured as the difference between the control and the ethanol group at single points of time. In addition, our study showed that ethanol should not be regarded as a general inducer of microsomal enzymes.

Alcoholism↗

PubMed1978

Lack of effect of fever on antipyrine oxidation in the rat.

The pharmacokinetics of 14C-antipyrine were studied in rats with fever induced by intracerebroventricular injections of prostaglandin E1. The rats were used as their own controls with at least 5 days between the control and the fever period. The effect of temperature on rates of antipyrine metabolism (oxidation followed by conjugation) and paracetamol metabolism (conjugation) was also tested in suspensions of isolated liver cells. Fever increased the biological half-life of antipyrine to 147% of control values (P less than 0.01) and the apparent volume of distribution to 113% of control values (P less than 0.05). In individual rats the increase in biological half-life was most counterbalanced by the increase in apparent volume of distribution, resulting in non-significant changes in the metabolic clearance of the drug. The half-life of antipyrine elimination in suspensions of isolated liver cells was not changed by increasing the temperature from 29 to 39 degrees C. The half-life of paracetamol elimination in suspensions of isolated liver cells decreased, however, when the temperature was increased from 29 to 39 degrees C. The results suggest that antipyrine oxidation was not influenced by temperature changes in the range of moderate fever and that temperature changes affected different types of metabolic reactions differently.

Animals↗

PubMedDate not supplied

Ethanol-induced increase in NADH-dependent monooxygenase activities of hepatic microsomal cytochrome P-450.

NADH-dependent hepatic microsomal monooxygenase activities were measured in the presence and absence of NADPH in material from adult male rats given ethanol in a liquid diet. Controls were given a liquid control diet (control group; lipid as substitute for ethanol) or rat chow (untreated group). Ethanol feeding elevated microsomal aniline hydroxylase activity and did not change ethylmorphine N-demethylase activity. NADH supported 21-24% of the NADPH-driven aniline hydroxylase activity in ethanol, control and untreated microsomes, but only about 6% of ethylmorphine N-demethylase activity. In the presence of NADPH, NADH gave 13-14% increase in aniline hydroxylase activity in microsomes from control and untreated rats, but only 3% in ethanol microsomes. In contrast, the presence of NADPH increased many times the effect of NADH on ethylmorphine N-demethylation with no striking difference between the groups. In another series of experiments, demethylation of 4-nitroanisole was elevated after ethanol feeding (4-fold with NADPH; 5-fold with NADH) and phenobarbital treatment (8-fold with NADPH, 2-fold with NADH). In the ethanol-induced activity, NADH and NADPH were less than additive. In the control and untreated and the phenobarbital-induced activities, NADH and NADPH were additive or possibly synergistic in driving the activity. Both ethanol and phenobarbital elevated cytochrome P-450; ethanol also elevated cytochrome b5 measured as NADH-reducible cytochrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Effect of reduced perfusion pressure and acetylcholine on local blood flow in tumors in the rat kidney.

The local blood flow (LBF) in a sarcoma and a hepatoma implanted into the rat kidney was examined during renal vasodilation, with and without increased total renal blood flow (RBF). Both tumor types had a control LBF of about 0.7 ml/min per g, i.e. 35 per cent or less as compared with the renal LBF, as simultaneously determined by the H2 gas clearance technique. The RBF averaged 4.6 ml/min per g as recorded electromagnetically. During about 20 mmHg reduction of renal arterial pressure the tumor LBF was maintained relative to the renal LBF, whether the RBF was autoregulated or not. Provided neoplastic vessels account for most of the vascular resistance to tumor blood flow, they must therefore possess autoregulatory ability. The tumor LBF was maintained when the RBF was maximally increased by continuous renal arterial infusion of acetylcholine. This may suggest that a neoplastic vessel vasodilatory response to acetylcholine prevented reduction of the tumor flow.

Acetylcholine↗

PubMedDate not supplied

Intraarterial doxorubicin infusion treatment with and without occlusion of the renal artery in rabbit renal VX-2 carcinoma. Establishing an animal model.

The aim of this investigation was to establish an animal model for studying fractionated intraarterial treatment of a rabbit kidney VX-2 carcinoma. As repeated catheterizations and drug infusions may cause vascular lesions, we wanted to find whether the rabbit renal artery could be catheterized several times within a short period of time with acceptable iatrogenic vascular trauma. Each of 3 groups of rabbits with implanted renal VX-2 carcinoma were treated 3 times with either 1) temporary renal artery occlusion combined with infusion (occlusion infusion) of a) physiologic saline (OIS) or b) doxorubicin (OID), or 2) with renal artery infusion of doxorubicin. OID was administered in 20 of 21 attempts, OIS in 21 of 24, and infusion of doxorubicin in 20 of 21 attempts. Renal arterial spasm was seen in 5 of 22 rabbits, rarely at the first catheterization, more frequently during the second and third. Permanent iatrogenic vascular trauma occurred in 4 of 15 rabbits after the second and third occlusion infusion. We conclude that the rabbit kidney with implanted VX-2 carcinoma may be a useful model for testing fractionation schemes for multiple intraarterial infusions of antineoplastic drugs.

Animals↗