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Biomedical subjects

G J Mulder

Publications and source records attributed to G J Mulder.

At least 163 records · Page 9Linked to original sources
PubMed1982

Cholestatic effect of harmol glucuronide in the rat. Prevention of harmol-induced cholestasis by increased formation of harmol sulfate.

Harmol, a phenolic compound of low molecular weight, is conjugated either with glucuronic acid or sulfate. A clear relationship is observed between the metabolism of harmol and the occurrence of cholestasis: high concentrations of harmol glucuronide in bile induced a complete stop of bile flow, both in the rat in vivo and in the perfused rat liver. Intravenous infusion of harmol (250 mumol/hr/kg b.wt.) in vivo in the rat considerably decreased the availability of sulfate and, consequently, the amount of harmol sulfate excreted in bile and urine; this decrease was compensated for by an increase in glucuronidation, which caused complete cholestasis when the concentration of harmol glucuronide in bile became of the order of 20 mM. A sufficient supply of sulfate by infusion of sodium sulfate prevented the decrease in sulfation and the increase in glucuronidation and no cholestasis occurred. Low sulfate availability in rats fed a low-protein diet decreased the time of harmol infusion required for cholestasis to occur. Alleviation of the cholestasis in low-protein diet-fed rats was observed when after 2 hr of infusion of harmol additional sulfate was supplied. In the single-pass perfused rat liver, cholestasis occurred when large amounts of harmol glucuronide were excreted in bile. When sulfation of harmol was inhibited by 2,6-dichloro-4-nitrophenol, cholestasis occurred at lower infusion rates of harmol. These data indicate that harmol glucuronide is cholestatic when its concentration in bile increases beyond a threshold concentration; the protein content of the diet may profoundly affect the occurrence of this toxic effect.

Alkaloids↗
PubMed1981

The oxidation of L- and D-cysteine to inorganic sulfate and taurine in the rat.

Oral administration of L-cysteine to rats (8 mmol/kg body wt.) caused a rapid increase of the concentration of cystine in serum, from less than 5 micro M in controls to about 200 micro M. Concomitantly, the serum concentration of inorganic sulfate increased, reaching a peak 2 h after L-cysteine administration; this level, twice the control level, was maintained for 4 h. Serum sulfate returned to control concentration 23 h after L-cysteine administration. The urinary excretion of inorganic sulfate during the 24 h after administration increased considerably, and 33% of the dose of L-cysteine was recovered as inorganic sulfate in urine. Consumption of comparable amounts of L-cysteine via the food caused the same increase in urinary excretion of sulfate, but did not increase the concentration of sulfate in serum. After oral administration of D-cysteine (8 mmol/kg body wt.), very high cystine levels were reached in serum (mean concentration about 1500 microM); the sulfate concentration was already maximal 30 min after administration. The increase in urinary excretion of sulfate after D-cysteine was also higher than after L-cysteine administration: 55% of the dose. Possible routes for the rapid degradation of D-cysteine to inorganic sulfate are discussed. The administration of L-cysteine also caused an increase the serum concentration of taurine, while methionine was not influenced. D-Cysteine did not increase the serum concentration of taurine, indicating that it is probably not or only slowly converted to taurine.

Administration, Oral↗
PubMed1981

Alteration of urinary levels of the carcinogen, N-hydroxy-2-naphthylamine, and its N-glucuronide in the rat by control of urinary pH, inhibition of metabolic sulfation, and changes in biliary excretion.

The hepatic metabolism of arylamine bladder carcinogens to N-hydroxy arylamine N-glucuronides, their excretion in the urine, and their subsequent acidic hydrolysis to highly carcinogenic and reactive N-hydroxy arylamines have been proposed as essential steps in arylamine-induced urinary bladder carcinogenesis. In this study, alteration of urinary pH, inhibition of metabolic sulfation, and blockage of biliary disposition were shown to profoundly affect the urinary excretion of the probable ultimate bladder carcinogen, N-hydroxy-2-naphthylamine (N-HO-2-NA) and its N-glucuronide conjugate. The normal pH of rat urine (6.7) was altered to 5.7 or 7.7 by administration of NH4Cl or NaHCO3 in the drinking water. Subsequent treatment with either 2-naphthylamine (2-NA) or 2-nitronaphthalene (2-NN) resulted in increased urinary levels of free N-HO-2-NA (relative to its N-glucuronide) in acidic urines and decreased relative amounts of free N-HO-2-NA in alkaline urines. In addition, 2-NN yielded 5--10-fold greater levels of urinary N-HO-2-NA and its N-glucuronide than rats given 2-NA; and 2-NA was not detected as a urinary metabolite of 2-NN. Some 12 additional metabolites of 2-NA and 2-NN were also found. Of these, 2-amino-1-naphthol and its sulfate and glucuronide conjugates were quantitated. From these data, 2-NA and 2-NN appear to share common metabolic pathways which yield free N-HO-2-NA as a putative ultimate urinary bladder carcinogen. Pentachlorophenol, a known inhibitor of hepatic sulfotransferases, was shown to cause a 2--3-fold increase in the urinary levels of N-HO-2-NA N-glucuronide and N-HO-2-NA from 2-NA-treated rats. Similarly, inhibition of the biliary excretion of 2-NA by bile duct ligation resulted in a 6-fold increase in total urinary N-HO-2-NfA. Furthermore, analyses of bile revealed that substantial amounts of N-HO-2-NA N-glucuronide, but not free N-HO-2-NA, were present. The role of urinary versus biliary excretion of N-hydroxy arylamines in relation to bladder and colon carcinogenesis is discussed.

2-Naphthylamine↗
PubMed1981

Role of sulfation in the formation of DNA adducts from N-hydroxy-2-acetylaminofluorene in rat liver in vivo. Inhibition of N-acetylated aminofluorene adduct formation by pentachlorophenol.

N-Hydroxy-2-acetylaminofluorene (N-OH-AAf) is metabolically converted into reactive N,O-esters which are capable of forming covalent adducts with DNA in rat liver in vivo. The effect of inhibiting one of the proposed pathways, N-O-sulfation, on DNA adduct formation was studied by using a specific sulfotransferase inhibitor, pentachlorophenol. Rats were pretreated with pentachlorophenol and, after 45 min, N-OH-AAF was administered. Four hours after dosing the animals were sacrificed and hepatic DNA was isolated. In DNA from control livers two acetylaminofluorene-and one aminofluorene-substituted deoxyguanosine adducts were found. The acetylaminofluorene derivatives, N-(deoxyguanosin-8-yl)-2--acetylaminofluorene and 3-(deoxyguanosin-N2-yl)-2acetylaminofluorene, accounted for 40% of the total binding in the hydrolyzed DNA. The aminofluorene adduct, N-(deoxyguanosin-8-yl)-2-aminofluorene, accounted for the remainder. In rats that were pretreated with pentacholorphenol, total DNA binding was decreased by 26%. The same three adducts were found, but the acetylaminofluorene adducts were now only 13% of the total, while the aminofluorene adduct accounted for 87%. The absolute amount of aminofluorene adduct was not altered as compared to control rats. These data demonstrate the involvement of N-O-sulfation in carcinogen-DNA binding and indicate that at least 70% of the acetylaminofluorene bound to deoxyguanosine in rat liver DNA, in vivo, is formed through N-O-sulfation of N-OH-AAF.

2-Acetylaminofluorene↗
PubMed1979

Absorption, serum levels and urinary excretion of inorganic sulfate after oral administration of sodium sulfate in the conscious rat.

The absorption of inorganic sulfate after ingestion was investigated in rats. After oral administration of Na235SO4, 35S radioactivity was measurable in plasma already after 15 min and its plasma concentration reached a peak after about 1.5--2 h. The 35S-radioactivity excreted in urine during 24 h after ingestion of Na235SO4 together with varying amounts of unlabelled Na2SO4 (0.25--5.0 mmol Na2SO4 per rat) indicated an almost complete absorption of inorganic sulfate from the gastrointestinal tract. Determination of the inorganic sulfate concentration in rat serum 2 h after oral administration of 5.0 mmol Na2SO4 revealed a three-fold increase in serum sulfate concentration. The data suggest a rapid and almost complete absorption of inorganic sulfate after oral administration in the rat. Its importance in relation to the sulfate availability for sulfate conjugation of drugs is discussed.

Administration, Oral↗
PubMed1979

Biliary and urinary excretion of drug conjugates: effect of diuresis and choleresis on excretion of harmol sulphate and harmol glucuronide in the rat.

1. Harmol (7-hydroxy-1-methyl-9H-pyrido [3,4b] indole) is converted to harmol sulphate and harmol glucuronide in the rat in vivo. Harmol sulphate is excreted mainly in urine, while harmol glucuronide is excreted about equally in bile and urine, when harmol is given intravenously. 2. In rats with ligated kidneys, only choleresis produced by glycodehydrocholate and dehydrocholate caused enhanced biliary excretion of harmol sulphate; harmol glucuronide was unaffected. Several other bile salts had no effect. 3. Mannitol diuresis markedly increased urinary excretion of harmol sulphate, and decreased its biliary excretion. Harmol glucuronide was much less affected. 4. Nafenopin pretreatment increased liver weight and bile flow, and enhanced biliary excretion of harmol sulphate at the expense of its urinary excretion. 5. For harmol sulphate, urine and bile are compensatory pathways of elimination that can be influenced by urine and bile flow changes through diuresis and choleresis.

Alkaloids↗
PubMed1979

Inhibition of sulfation of phenols in vivo by 2,6-dichloro-4-nitrophenol: selectivity of its action in relation to other conjugations in the rat in vivo.

The effect of 2,6-dichloro-4-nitrophenol, an inhibitor of the sulfation of the phenolic compound harmol in vivo, on the sulfation of other phenolic substances and on various conjugation reactions has been studied in the rat in vivo. Compounds chemically related to 2,6-dichloro-4-nitrophenol were also tested as sulfation inhibitors. 2,6-Dichloro-4-nitrophenol inhibited the sulfation of phenol while it had no effect on biliary excretion of dibromosulphthalein, glucuronidation of phenolphthalein, acetylation of procainamide ethobromide or glutathione conjugation of ethacrynic acid. It is concluded that of these conjugation reactions sulfation is inhibited selectively at the dose level used. Some phenols with chloro- or nitro-substituents effectively inhibited the sulfation of harmol but to a lesser extent than 2,6-dichloro-4-nitrophenol. Many other phenols did not affect the conjugation of harmol, which is both glucuronidated and sulfated.

Animals↗
PubMed1978

Metabolism of inorganic sulphate in the isolated perfused rat liver. Effect of sulphate concentration on the rate of sulphation by phenol sulphotransferase.

1. The metabolism of inorganic [(35)S]sulphate (Na(2) (35)SO(4)) was studied in the isolated perfused rat liver at three initial concentrations of inorganic sulphate in the perfusion medium (0, 0.65 and 1.30mm), in relation to sulphation and glucuronidation of a phenolic drug, harmol (7-hydroxy-1-methyl-9H-pyrido[3,4-b]indole). 2. [(35)S]Sulphate rapidly equilibrated with endogenous sulphate in the liver. It was excreted in bile and reached, at the lowest concentration in the perfusion medium, concentrations in bile that were much higher than those in the perfusion medium; at the higher sulphate concentrations, these concentrations were equal. The physiological concentration of inorganic sulphate in the liver, available for sulphation of drugs, is similar to the plasma concentration. 3. At zero initial inorganic sulphate in the perfusion medium, the rate of sulphation was very low and harmol was mainly glucuronidated. At 0.65mm-sulphate glucuronidation was much decreased and considerable sulphation took place, indicating efficient competition of conjugation by sulphation. At 1.30mm-sulphate the sulphation increased still further. 4. The results suggest that an important factor in sulphation is the relatively high K(m) of synthesis of adenosine 3'-phosphate 5'-sulphatophosphate (the co-substrate of sulphation) for inorganic sulphate, which is of the order of the plasma concentration of inorganic sulphate. The steady-state adenosine 3'-phosphate 5'-sulphatophosphate concentration may determine the rate of sulphate conjugation of drugs in the rat in vivo.

Animals↗