Showing papers on "Metabolite published in 1972"

Liver microsomal metabolism of aflatoxin B 1 to a reactive derivative toxic to Salmonella typhimurium TA 1530.

Abstract: Summary A reduction in the survival of Salmonella tryphimurium TA 1530 was observed when the bacteria were incubated with aflatoxin B 1 , rat liver microsomes, and a reduced nicotinamide adenine dinucleotide phosphate-generating system. The lethality appeared to depend on the formation of a metabolite of aflatoxin B 1 by a mixed-function oxygenase system. The killing was very rapid; only 1% of the bacteria were able to form colonies after 2 min of incubation with large amounts of microsomes and aflatoxin B 1 . Attempts to separate the toxic metabolite from the microsomal system have not been successful. Toxic metabolites for S. typhimurium TA 1530 were also formed if aflatoxin B 1 was replaced by either aflatoxin G 1 or sterigmatocystin in the microsome-mediated toxicity assay. Except for aflatoxicol, the derivatives that were tested either had much less activity or were inactive. The livers from a number of other species of rodents and a single autopsy sample of human liver also were active in the microsome-mediated aflatoxin B 1 toxicity assay. The addition of RNA or DNA to the incubation mixture inhibited the killing of the bacteria. The RNA (which was reisolated after its incubation with aflatoxin B 1 ), liver microsomes, and a reduced nicotinamide adenine dinucleotide phosphate-generating system showed a low, broad absorption, with a maximum at 366 to 370 nm. This high wavelength absorption was not removed by Sephadex G-10 chromatography of the RNA or by extraction procedures and appeared to be attributable to covalently bound aflatoxin B 1 toxicity assay. The formation of the conjugated RNA was dependent on reduced nicotinamide adenine dinucleotide phosphate and was inhibited by the addition of aniline; the amount formed was a function of the activity of the mixed-function oxygenases in the incubation mixture. On the basis of the data presented, it is tentatively suggested that the derivative that is toxic to S. typhimurium TA 1530 and the one that reacts with nucleic acids are identical. The possible relationship of this derivative to the hepatocarcinogenicity of aflatoxin B 1 is discussed.

Free tryptophan in plasma and brain tryptophan metabolism.

Abstract: SYNTHESIS in the brain of the putative transmitter 5-hydroxytryptamine (5HT) is influenced by the concentration of tryptophan; the rate limiting step in 5HT synthesis is the hydroxylation of tryptophan1 by tryptophan hydroxylase, which is normally unsaturated with substrate2. Often when 5HT turnover in the rat brain increases—as indicated by higher concentrations of its metabolite 5-hydroxyindoleacetic acid (5HIAA)—there is a corresponding increase in brain tryptophan. This occurs when the rats are given various drugs known to increase brain 5HT synthesis3, deprived of food4,5, or immobilized5. Therefore the control of brain tryptophan concentration is clearly of some importance.

Metabolism of [14C]methamphetamine in man, the guinea pig and the rat

Abstract: 1. The metabolites of (+/-)-2-methylamino-1-phenyl[1-(14)C]propane ([(14)C]methamphetamine) in urine were examined in man, rat and guinea pig. 2. In two male human subjects receiving the drug orally (20mg per person) about 90% of the (14)C was excreted in the urine in 4 days. The urine of the first day was examined for metabolites, and the main metabolites were the unchanged drug (22% of the dose) and 4-hydroxymethamphetamine (15%). Minor metabolites were hippuric acid, norephedrine, 4-hydroxyamphetamine, 4-hydroxynorephedrine and an acid-labile precursor of benzyl methyl ketone. 3. In the rat some 82% of the dose of (14)C (45mg/kg) was excreted in the urine and 2-3% in the faeces in 3-4 days. In 2 days the main metabolites in the urine were 4-hydroxymethamphetamine (31% of dose), 4-hydroxynorephedrine (16%) and unchanged drug (11%). Minor metabolites were amphetamine, 4-hydroxyamphetamine and benzoic acid. 4. The guinea pig was injected intraperitoneally with the drug at two doses, 10 and 45mg/kg. In both cases nearly 90% of the (14)C was excreted, mainly in the urine after the lower dose, but in the urine (69%) and faeces (18%) after the higher dose. The main metabolites in the guinea pig were benzoic acid and its conjugates. Minor metabolites were unchanged drug, amphetamine, norephedrine, an acid-labile precursor of benzyl methyl ketone and an unknown weakly acidic metabolite. The output of norephedrine was dose-dependent, being about 19% on the higher dose and about 1% on the lower dose. 5. Marked species differences in the metabolism of methamphetamine were observed. The main reaction in the rat was aromatic hydroxylation, in the guinea pig demethylation and deamination, whereas in man much of the drug, possibly one-half, was excreted unchanged.

Metabolism of apigenin and related compounds in the rat. Metabolite formation in vivo and by the intestinal microflora in vitro.

Abstract: 1. The metabolism of a group of polyphenols related in structure to myricetin (3,5,7,3′,4′,5′-hexahydroxyflavone), including myricetin, myricitrin, 3,4,5-trihydroxyphenylacetic acid, delphinidin, robinetin, tricetin, tricin, malvin and 5,7-dihydroxy-3′,4′,5′-trimethoxyflavone, has been studied both in vivo after oral administration to the rat and in vitro in cultures of micro-organisms derived from the intestine of the rat. 2. It was shown that the rat intestinal microflora are able to degrade compounds of this group to the ring-fission products observed in urine after oral administration of the specific flavonoid. 3. All flavones and flavonols possessing free 5- and 7-hydroxyl groups in the A ring and a free 4′-hydroxyl group in the B ring gave rise to ring-fission products that included 3′,5′-dihydroxyphenylacyl derivatives. 4. The metabolites 3,5-dihydroxyphenylacetic acid, 3-hydroxyphenylacetic acid, 3,5-dihydroxyphenylpropionic acid and 3-hydroxyphenylpropionic acid were isolated and identified by chromatographic and spectral methods. 5. On anaerobic incubation in a thioglycollate medium it was shown that intestinal micro-organisms can effect cleavage of glycosidic bonds, ring fission of certain flavonoid molecules showing 3′,4′,5′-trihydroxyphenyl substitution and dehydroxylation of certain flavonoid metabolites. 6. The urinary excretion of the metabolites 3,5-dihydroxyphenylacetic acid and 3-hydroxyphenylacetic acid was completely abolished when neomycin-treated rats were used.

Enzymatic Metabolism of Cyclophosphamide and Nicotine and Production of a Toxic Cyclophosphamide Metabolite

Abstract: Summary Cyclophosphamide is converted by enzymes of mouse liver into two metabolites. Production of the first (aldophosphamide), which is uncharged, requires TPNH, is inhibited by CO, and is accomplished predominantly by the microsomal fraction. With the microsomal enzyme, the Km for cyclophosphamide is 0.5 mm; nicotine, atropine, ephedrine, apomorphine, and cocaine are potent inhibitors. Phenobarbital, cytochrome c, 2-diethylaminoethyl-2,2-diphenylvalerate, and some steroid hormones also inhibit the reaction. Aldophosphamide is very toxic, as judged by inhibition of clone formation of human epidermoid carcinoma No. 2 cells and by toxicity to L1210 leukemia cells. The initial metabolite is further converted to 2-carboxyethyl N,N-bis-(2-chloroethyl)phosphorodiamidate (carboxyphosphamide) by an enzyme in the soluble portion of the cell. This enzyme can be replaced by purified aldehyde oxidase (aldehyde:oxygen oxidoreductase, EC 1.2.3.1). Carboxyphosphamide, which has little or no antitumor effect, is much less toxic to clone formation of human epidermoid carcinoma No. 2 cells and to L1210 cells. Administration of pyridoxal, which could saturate the endogenous aldehyde oxidase and thus delay the production of carboxyphosphamide, in combination with cyclophosphamide increases the life-span of mice implanted with L1210 cells. The metabolic conversion of nicotine to cotinine by liver proceeds in the same manner as cyclophosphamide oxidation. Nicotine is also oxidized by an amine oxidase to nicotine 1′-oxide. Lung homogenates accomplish the initial oxidation of both cyclophosphamide and nicotine but do not metabolize the products further. Kidney homogenates contain the amine oxidase producing nicotine 1′-oxide. Several other tissues are not active in the metabolism of either cyclophosphamide or nicotine.

Comparative Pharmacokinetics of Daunomycin and Adriamycin in Several Animal Species

Abstract: Summary The physiological disposition of adriamycin and daunomycin has been studied in several animal species. Both drugs were rapidly cleared from plasma, deposited in tissues, and then excreted slowly. Drug and metabolites were excreted via the bile and urine. Daunomycin was extensively metabolized by mice, rats, dogs, and hamsters, whereas no evidence was obtained for the metabolism of adriamycin in rats and mice. Hamsters metabolized adriamycin to an aglycone. The metabolite of daunomycin in all species appeared identical to daunorubicinol, described by Bachur and Gee. In hamsters, daunorubicinol as well as another metabolite of daunomycin were observed. This unknown metabolite, D x , appeared to be an aglycone but not the aglycone of daunomycin or daunorubicinol. The aglycone, D x , was also observed in several tissues of rats and mice that were exposed to hypobaric stress.

1,25-dihydroxycholecalciferol: metabolite of vitamin D3 active on bone in anephric rats.

Abstract: Nephrectomy prevents completely the bone calcium mobilization response to 25-hydroxycholecalciferol. In contrast it does not prevent this response to 1,25-dihydroxycholecalciferol. Because it is known that the kidney is the site of 1,25-dihydroxycholecalciferol formation, these results provide evidence that 1,25-dihydroxycholecalciferol or a further metabolite thereof and not 25-hydroxycholecalciferol is the metabolically active form of vitamin D(3) responsible for bone calcium mobilization.

On the Metabolism of Prostaglandin F2α in Female Subjects

Abstract: Laboratory experimentation was conducted on the metabolism of PG(prostaglandin)F2alpha in a female subject. Laboratory preparation of the chemicals involved is described in detail. Tritium-labelled PGF2alpha was administered intravenously in a female subject and collection of venous blood from the contralateral arm was started simultaneously and continued for 10 minutes after completion of the injection. This collected blood was submitted to a number of laboratory analytic procedures in order to follow the initial transformations through PGF2alpha metabolism. 2 radioactive products--1 major metabolite and 1 minor metabolite--appeared in the blood and were identified. The structures of these 2 metabolites are analyzed and reported. Although the pathways in the formation of these 2 metabolites have not been studied in humans the 1st step is believed to be enzymatic oxidation of the allylic alcohol group at C-15 reduction of the Delta 13 double bond and subsequent reduction of the oxo group at C-15.

Metabolism and Biochemistry of Mycophenolic Acid

Abstract: Summary Mycophenolic acid is a new, experimental oncolytic agent that interferes in the interconversion of inosine, xanthosine, and guanosine monophosphates. IMP dehydrogenase, which converts IMP → XMP, and GMP synthetase, which converts XMP → GMP, are inhibited by mycophenolic acid. The IMP dehydrogenase from a human adenocarcinoma of the colon was more sensitive to mycophenolic acid than was the enzyme from murine tumors. There is a correlation between the sensitivity of experimental tumors to mycophenolic acid and the relative activities of β-glucuronidase and hypoxanthine-guanine phosphoribosyltransferase. Mycophenolic acid glucuronide is unable to cross the cell membrane; therefore the intracellular concentration of the free acid depends on the rate of hydrolysis of the glucuronide by β-glucuronidase. A mechanism of resistance to mycophenolic acid is the circumvention of the block in the nucleotide interconversion. GMP is resupplied by conversion of guanine to its nucleotide by hypoxanthine-guanine phosphoribosyltransferase. In tumors resistant to mycophenolic acid, the transferase activity is high; in tumors sensitive to mycophenolic acid, the activity is low. The relative activities of these two enzymes in tumors in man may indicate the potential effectiveness of mycophenolic acid in humans. Mycophenolic acid is initially secreted into the bile and excreted in the urine and feces of animals. 14CO2 was not detected in the expired air of mice, rats, or marmosets given 14C-labeled mycophenolic acid. The only metabolite detected in mice, rats, rabbits, and humans was mycophenolic acid glucuronide.

Biologic effects of 1,25-dihydroxycholecalciferol (a highly active vitamin D metabolite) in acutely uremic rats

Abstract: A B S T R A C T The development of a vitamin D-resistant state in the course of renal failure may be responsible for reduced intestinal absorption of calcium and an impaired response of skeletal tissue. Moreover, the kidney has been shown to carry out the conversion of 25-hy

The fate of (14C)phenol in various species.

Abstract: 1. [14C]Phenol has been administered to man (dose, 0.01 mg/kg) and 18 animal species (25 mg/kg) and the urine examined for metabolites by radiochromatogram scanning.2. In three men 90% of an oral dose was excreted in 24 h mainly as phenylsulphate (77% of 24 h excretion) and phenylglucuronide (16%) with very small amounts of quinol sulphate and glucuronide.3. Four metabolites, the sulphates and glucuronides of phenol and quinol, were found in the urine of the rodents, the rat, mouse, jerboa, gerbil, hamster, lemming and guinea-pig after an oral dose of phenol.4. Three metabolites were excreted by some species, namely, phenol and quinol glucuronides and phenylsulphate by the squirrel monkey and capuchin monkey, and phenol and quinol sulphates and phenylglucuronide by the ferret, dog, hedgehog and rabbit.5. Two metabolites were excreted by the rhesus monkey, fruit bat and hen (phenylsulphate and phenylglucuronide) and by the cat (phenylsulphate and quinol sulphate). One metabolite (phenylglucuronide) only wa...

11-Hydroxy-Δ9-tetrahydrocannabinol: Pharmacology, Disposition, and Metabolism of a Major Metabolite of Marihuana in Man

Abstract: 11-Hydroxy-Delta(9)-tetrahydrocannabinol, administered intravenously to man, produces psychologic and pharmacologic effects that persist for several hours. The drug and its metabolites are excreted in urine and feces for more than 1 week. The pharmacology, disposition, and metabolism of 11-hydroxy-Delta(9)-tetra-hydrocannabinol mimic that of Delta(9)-tetrahydrocannabinol, thus providing evidence that Delta(9)-tetrahydrocannabinol (the major active component of marihuana) is converted to the 11-hydroxy compound in man, the latter compound being responsible for the effects.

Effect of L-Tryptophan on Brain Serotonin Metabolism in Depressed Patients

Abstract: Cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin, was assayed in a group of five depressed patients before and during treatment withL-tryptophan, with and without probenecid.L-tryptophan administration was associated with a slight increase in the baseline levels of 5-HIAA, but caused a twofold to threefold increase in the accumulation of 5-HIAA in the cerebrospinal fluid following probenecid administration. The apparent increase in brain serotonin turnover produced byL-tryptophan in these patients was not accompanied by an improvement in depression.

Warfarin and the Inhibition of Vitamin K Activity by an Oxide Metabolite

Abstract: THE isolation and identification of phylloquinone oxide as a metabolite of vitamin K1 in rats given warfarin (3-α-phenyl-β-acetylethyl-4-hydroxycourmarin) led us to investigate the possibility that the oxide is involved in the action of the vitamin or anticoagulant or both1. We knew that phylloquinone oxide had approximately the same activity as vitamin K1 in vitamin K deficient rats but was ineffective in those treated with warfarin2. Evidence that the activity of the oxide was due to its conversion to vitamin K1, a reaction inhibited by warfarin in vivo2, prompted us to investigate the possibility that phylloquinone oxide, because of structural similarity, may be an inhibitor of vitamin K1 and that warfarin exerts its anticoagulant effect by causing accumulation of the oxide.

The role of aryl hydrocarbon hydroxylase in 7,12-dimethylbenz(a)- anthracene skin tumorigenesis, on the mechanism of 7,8-benzoflavone inhibition of tumorigenesis.

Abstract: Summary Aryl hydrocarbon hydroxylase of mouse skin is inducible by benz(a)anthracene or 7,12-dimethylbenz(a)anthracene (DMBA) and is inhibited by 7,8-benzoflavone. 7,8-Benzoflavone inhibits the formation of covalently bound complexes of DMBA with DNA, RNA, and protein and also inhibits tumor formation caused either by a single application of DMBA, followed by croton oil treatment, or by the repeated application of DMBA. These results indicate that DMBA requires metabolic activation by aryl hydrocarbon hydroxylase for its carcinogenic activity. The inhibitory effect of 7,8-benzoflavone is limited to its application within 12 hr of administration of the DMBA, suggesting that the metabolic activation of DMBA is completed within 12 hr. The level of aryl hydrocarbon hydroxylase and DMBA tumorigenesis varies markedly in different mouse strains, indicating either that there are genetic differences in the profile of DMBA metabolite formation or that metabolic activation is necessary but not sufficient for DMBA tumorigenesis.

Glucoreceptor mechanisms in islets of Langerhans.

Abstract: A widely accepted concept has been that metabolites of glucose or factors associated with glucose metabolism, rather than glucose itself, trigger insulin release from the β cells. If this concept is correct, levels of metabolites or cofactors or of both should change within seconds of the glucose pulse. To examine the hypothesis, glucose, glucose-6-P, 6-P-gluconate, fructose-l,6-P2 plus triose-P, 3-P-glycerates plus P-enolpyruvate, ATP, ADP and P-creatine were measured in slices of individual rat islets after intravenous infusion of glucose in vivo or perfusion of the isolated pancreas with glucose in vitro. Tissue samples were obtained by quickfreezing methods as early as fifteen seconds and as late as sixty minutes following the glucose load. Insulin levels in serum and perfusate were measured concomitantly. Insulin levels in peripheral blood rose within one minute of injection of glucose in vivo. Penetration of glucose, although very rapid, was carrier-mediated. Most of the metabolites and cofactors measured were unchanged during the first five minutes of glucose infusion. After one hour of hyperglycemia there was a marked rise in all metabolites and cofactors except ATP. In the perfused pancreas, insulin secretion increased within 0.5 minute of the glucose stimulus and the typical biphasic response was observed. The glucose content of islets increased threefold within 0.25 minute and sixfold within 0.5 minute. The levels of all other metabolites measured were virtually unchanged during the early phase of the endocrine response, in spite of the eightfold increment in the glucose of the medium and the almost tenfold rise of insulin release. The constancy of the islet's metabolite pattern when the islets were exposed to high glucose—particularly during the early transition phase—is remarkable, since glycolytic flux was supposedly increased severalfold. The fact that the metabolite profile of the islets is so precisely maintained within a narrow range makes it unlikely that any of the metabolites measured might serve as triggers for insulin release. It is more likely that the glucose molecule itself exerts its releasing action by stimulating glucoreceptors located on the cell membrane.

Pharmacokinetic studies of minoxidil

Abstract: The disposition of minoxidil, a new direct arterial vasodilator and potent antihypertensive, was studied in 7 hypertensive patients Following oral administration of 14C-labeled minoxidil, there was a rapid removal of the drug with a plasma half-life of 42 hours The radioactive label was recovered quantitatively in the urine, predominantly in the form of 3 metabolites The major metabolite in the first 12 hours after giving the drug was a glucuronide conjugate The other 2 metabolites have not been identified but appeared to be excreted predominantly after the first 12 hours, when minoxidil had been essentially cleared from the circulating blood These observations suggest a dissociation between the drug in circulating blood and its pharmacologic activity Since the prolonged hypotensive response to minoxidil cannot be attributed to slow removal, we suggest that it may be exerting a persistent effect on receptor sites

A gas chromatographic assay for ketamine in human plasma.

Abstract: A highly sensitive, quantitative assay procedure for ketamine and two of its metabolites, based upon gas–liquid chromatography of a heptafluorobutyryl derivative, has been developed. No appreciable interference occurred with procaine, atropine, meperidine or promethazine. Anesthetic doses in man (iv) produced ketamine plasma levels above 1 μg/ml, with a biological half-life of 17 min. The presence of the N-dealkylated metabolite of ketamine in human plasma was clearly demonstrated.

Trichloroethylene exposure and trichloroethylene metabolites in urine and blood

Abstract: After trichloroethylene (Tri) inhalation the metabolite trichloroethanol (TCE) is excreted rapidly in the urine, while trichloroacetic acid (TCA) accumulates in the organism due to a high plasma protein binding rate. After exposure of 5 volunteers to 50 ppm Tri for 6 h, 50 μg/ml TCA is found in the plasma at the end of the 5th exposure day, the amount of TCE present in the blood amounting to not more than 2.3 μg/ml. Instead of the previously used control of TCE + TCA in the urine, it is suggested to determine the metabolites in the blood by means of a gas Chromatographic micro technique which provides a reliable criterion of the preceding Tri exposure.