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Biomedical subjects

M A Collins

Publications and source records attributed to M A Collins.

At least 109 records · Page 6Linked to original sources
PubMed1985

Evidence for separate pathways of transport of newly synthesized and preformed cholesterol into bile.

Marked kinetic differences were observed when hepatic newly synthesized cholesterol and preformed cholesterol were separately radiolabeled and separately traced into bile. Whereas newly synthesized cholesterol was not evenly distributed throughout the liver but was preferentially secreted into bile, preformed cholesterol was in near-complete equilibrium in the whole liver and bile. Furthermore, whereas newly synthesized cholesterol in bile originated from the interior of the hepatocyte, results suggest that biliary preformed cholesterol may be transported directly from the blood through the plasma membrane of the hepatocyte and secreted from the canaliculus without first entering the interior of the cell and mixing with newly synthesized cholesterol.

Animals↗
PubMed1985

Beta-carboline analogues of N-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP): endogenous factors underlying idiopathic parkinsonism?

A remarkable structural similarity exists between the parkinsonian neurotoxin, N-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), and 2-[N]-methyl-tetrahydro-beta-carboline (2M-THBC), a tryptamine-derived alkaloid which can be biosynthesized in brain. To explore whether the beta-carboline also has neurotoxic effects, owl monkeys were treated daily with MPTP or 2M-THBC. Acute behavioral similarities were seen, but 2M-THBC did not induce persistent parkinsonism, nor did it cause apparent loss of nigral cells. However, 2M-THBC resembled MPTP in reducing 3,4-dihydroxyphenylacetic acid levels in caudate and in altering levels of serotonin and 5-hydroxyindoleacetic acid in substantia nigra. These limited similarities should be considered in the light of relationships between neurotoxicity, MPTP versus 2M-THBC oxidation, and the chronicity of human Parkinson's disease. We suggest that N-methylated beta-carboline species, possibly accumulating during stress and aging, could well be causative factors in parkinsonism.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Cholesterol exchange and synthesis in the live rat.

The turnover of plasma cholesterol and de novo cholesterol synthesis were measured simultaneously in the live rat, immediately after administration of [3H]water together with a large volume exchange transfusion of whole blood prelabeled with [14C]cholesterol. It was possible to separate the exchange of unesterified cholesterol from the uptake and secretion of lipoprotein cholesteryl ester, and also to assess the impact of plasma cholesterol exchange on the measurement of in vivo rates of cholesterolgenesis by individual tissues. Cholesterol was measured by an HPLC procedure that effectively separated cholesterol from other structurally similar sterols, and synthesis was determined by the incorporation of [3H]water into cholesterol. Plasma unesterified cholesterol turnover was multiphasic and exceedingly rapid (initial T1/2, 4.1 min) in contrast to the near linear and much slower turnover of plasma cholesteryl ester (initial T1/2, 59.4 min). Plasma unesterified cholesterol equilibrated with different tissues at different rates, with the liver and adrenal equilibrating most rapidly. Full equilibration of plasma unesterified cholesterol was not achieved with any tissue during the course of this study. For rapidly exchanging tissues like the liver, which was responsible for about 60% of plasma unesterified cholesterol exchange, unesterified cholesterol appeared to be kinetically compartmentalized into rapidly, and much less rapidly, exchangeable pools. After [3H]water administration, the content of newly synthesized cholesterol was greatest in the liver, adrenal, and intestine, and appreciably lower in all other tissues studied. Hepatectomy and intestinal resection resulted in a profound reduction of newly synthesized cholesterol in the plasma and adrenal, but no certain change in the already low amounts at other sites. Thus, while it is clear that appreciable amounts of newly synthesized cholesterol in the adrenal were derived from the plasma by exchange, it was not possible to make this assessment for other selected individual tissues. When, however, newly synthesized cholesterol was determined in the total mass of all extrahepatic and extraintestinal tissues together, exchange could be calculated to account for close to 50% of the new cholesterol recovered in the carcass (in studies of 60 min duration). After correcting for exchange, the liver accounted for 82% of all newly synthesized cholesterol, the intestine for about 10%, and the remaining tissues of the body for just 9%. These results are in marked contrast to recent findings of others and demonstrate that in the live rat cholesterol synthesis is principally confined to the liver.

Animals↗
PubMed1984

Gas chromatographic analysis of endogenous catecholamines, phenolic amines and derived isoquinolines using short glass capillary columns and electron-capture detection.

A gas chromatographic method is described for the concomitant separation and analysis of catecholamines, catecholamine or 3,4-dihydroxyphenylethylamine condensation products (tetrahydroisoquinolines), and their isomeric mono-O-methyl (phenolic) metabolites which may be present in neuronal tissues, utilizing short glass capillary columns and electron-capture detection. Isomeric phenolic amines that were not generally separable with conventional-packed gas chromatographic columns were rapidly resolved on the capillary system, and with their catecholamine or catechol isoquinoline precursors, quantitated with high sensitivity (0.25-7.0 pg) and reproducibility. Key steps in the approach with tissues include initial amine isolation with a weak cation-exchange resin (BioRex-70), fluoracyl derivative formation, and brief washing of the derivatives with ammonium phosphate buffer (pH 5.8) just prior to capillary analysis; overall recoveries of amines or alkaloids added to rat brain homogenates ranged from 79% to 89%. Application of the method is demonstrated in an assay of endogenous dopamine in rat corpus striatum and hypothalamus. This new procedure should complement and in some instances may be preferred over liquid chromatographic assays for catecholic and phenolic amines and isoquinolines, and ought to be applicable to mass spectrometric detectors as well.

Animals↗
PubMed1984

Effects of catecholamine-related mammalian alkaloids on spontaneous and vasopressin-induced behavior in mice.

Heterocyclic catechol derivatives (tetrahydroisoquinoline alkaloids) are known to be formed endogenously via condensation of the catecholamines with carbonyl compounds. In this study, the effects of a variety of representative simple isoquinolines, benzyl isoquinolines, bicyclic isoquinoline-derived alkaloids (pavines and isopavines), an aporphine and berberine were investigated after intracerebroventricular injection in mice. Most (thirteen) of the alkaloids studied were found to induce significant alterations in three behavioral parameters (immobility, grooming and scratching behavior). In addition, the stereotypic scratching behavior elicited by central injection of arginine-vasopressin (AVP) was significantly antagonized by only one of these, 6-O-methyl-tetrahydropapaveroline (6-O-methyl-THP). To a lesser extent, (-)THP and the pavine, (+/-)bisnorargemonine, were also effective. That this rather specific effect did not involve opioid receptors was indicated by the failure of naloxone to reverse the antagonism by 6-O-methyl-THP.

Alkaloids↗
PubMed1984

Sustained induction of hepatic xenobiotic metabolising enzyme activities by phenobarbitone in C3H/He mice: relevance to nodule formation.

Phenobarbitone (PB) was administered to male C3H/He mice at a dose of 85 mg/kg/day in a semisynthetic diet for up to 90 weeks. Throughout the treatment period a sustained induction of a number of parameters of hepatic Phase I and Phase II xenobiotic metabolism was observed. Histological examination revealed hypertrophy of the centrilobular cells of the liver lobule in PB treated mice and after 25 weeks small basophilic nodules were found in control and PB treated animals. In addition eosinophilic nodules, which were often large, developed in PB treated mice. Xenobiotic metabolising enzyme activities in large excised nodules after 70 or 90 weeks of PB treatment were either similar to or greater than those present in surrounding host tissue. Both phenobarbitone- and polycyclic hydrocarbon-type mixed function oxidase enzyme activities were induced in large nodules. In conclusion, PB produced a sustained induction of xenobiotic metabolising enzymes both in host tissue and in large eosinophilic nodules. The formation of these nodules in C3H/He mice was thus not associated with any failure of induction of hepatic xenobiotic metabolism.

Animals↗
PubMed1983

Catecholamine-derived tetrahydroisoquinolines: O-methylation patterns and regional brain distribution following intraventricular administration in rats.

The metabolism of 6,7-dihydroxy (catecholic)-1,2,3,4-tetrahydroisoquinolines (TIQs) is of interest because the heterocyclic substances may form in mammals normally or during certain disease via condensations of catecholamines (CAs) with aldehydes or alpha-keto acids. With a specific capillary gas chromatography procedure and confirmatory liquid chromatographic assays, we have determined the structural isomers and relative amounts of mono-O-methylated (phenolic) TIQ metabolites in several rat brain regions 40 min following the acute intracerebroventricular injection of four structurally related catecholic TIQs. In sharp contrast with the established selective m-O-methylation of dopamine (DA) by catechol-O-methyltransferase in brain, the two simple TIQs derived from DA produced predominantly or even exclusively the metabolic isomer arising from methylation of the original p-hydroxyl group (7-O-methylation). In three catecholaminergic brain regions examined, the 7-O-methyl isomer was the only detectable phenolic metabolite of (+/-) salsolinol-1-carboxylic acid (a condensation product of DA and pyruvic acid) and, as first noted by Bail et al. (1980), constituted 95% of the two possible isomeric mono-O-methyl metabolites of (+/-) salsolinol (TIQ derivative of DA and acetaldehyde). Though less, the 7-O-methyl isomers still were a significant proportion (40-55%) of the two mono-O-methylated metabolites of (+/-) 4-hydroxy-desmethylsalsolinol (a TIQ derived from norepinephrine and formaldehyde), or of the DOPA/acetaldehyde-derived TIQ, (cis) salsolinol-3-carboxylic acid. In the time frame of the study, all four administered TIQs showed higher levels in hypothalamus than in striatum or hippocampus, with the two carboxylated alkaloids displaying the greatest differences.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Studies on the effects of orally administered dicyclohexyl phthalate in the rat.

The oral administration of 500-2500 mg/kg/day dicyclohexyl phthalate (DCHP) to young male Sprague-Dawley rats for 7 days resulted in liver enlargement and induction of some parameters of hepatic xenobiotic metabolism. Additional studies indicated that the hepatic enzyme induction resembled that of sodium phenobarbitone rather than that of polycyclic hydrocarbons. Morphological examination of the livers of DCHP treated rats revealed centrilobular cell hypertrophy and ultrastructural examination demonstrated marked proliferation of the smooth endoplasmic reticulum. Mitochondrial structure and numbers of peroxisomes (microbodies) were not affected. DCHP treatment did not affect kidney and testes weights but some histological evidence of testicular damage was obtained with 2500 mg/kg/day of DCHP. The metabolites of DCHP, namely monocyclohexyl phthalate (MCHP) and cyclohexanol, also induced certain parameters of hepatic xenobiotic metabolism. MCHP, but not cyclohexanol also produced marked testicular atrophy. It is concluded that DCHP is a weak drug-type inducer of hepatic xenobiotic metabolism in the rat and the hepatic effects of this phthalate diester are different from those of di-(2-ethylhexyl) phthalate.

Animals↗
PubMed1982

Studies on the metabolism of dimethylnitrosamine in vitro by rat-liver preparations. II. Inhibition by substrates and inhibitors of monoamine oxidase.

1. The metabolism of dimethylnitrosamine (DMN) to formaldehyde by rat-hepatic postmitochondrial supernatant fractions has been compared with the activities of several cytochrome P-450-dependent mixed-function oxidase enzymes and the Ziegler mixed-function amine oxidase enzyme (EC 1.14.13.8). 2. A variety of monoamine oxidase (MAO, EC 1.4.3.4) inhibitors of diverse chemical structure inhibited the metabolism of DMN. In parallel studies a number of MAO substrates, but not their deaminated products, also inhibited DMN metabolism, whereas substrates of diamine oxidase were ineffective. 3. At concentrations which inhibited DMN metabolism several MAO substrates and inhibitors did not inhibit the N-oxidation of N, N-dimethylaniline and an inhibitor and an activator of the Ziegler enzyme had no corresponding effect on DMN metabolism. 4. The metabolism of DMN and a number of MAO enzyme activities were stable to storage under conditions where mixed-function oxidase enzymes were not. 5. These results are consistent with the suggestion that DMN may, at least in part, be metabolized by hepatic enzyme(s) not dependent on cytochrome P-450 and that a microsomal amine oxidase enzyme, unrelated to the Ziegler enzyme, may be involved in the hepatic degradation of this nitrosamine. The present data does, however, suggest a role for microsomal NADPH-cytochrome c reductase in hepatic DMN metabolism.

Amine Oxidase (Copper-Containing)↗
PubMed1982

Studies on the metabolism of dimethylnitrosamine in vitro by rat-liver preparations. III. Effect of cobaltous chloride treatment.

1. The effects of CoCl2 administration to rats on xenobiotic metabolism, dimethylnitrosamine (DMN) metabolism to formaldehyde and methanol, and monoamine oxidase (MAO) enzyme activities in hepatic subcellular fractions have been studied. 2. CoCl2 treatment markedly decreased hepatic mixed-function oxidase enzyme activities and microsomal cytochrome P-450 content. In contrast, the N-oxidation of N, N-dimethylaniline and the activity of microsomal NADPH-cytochrome c reductase was unaffected. 3. The metabolism of DMN to formaldehyde by postmitochondrial supernatant fractions was decreased at substrate concn. of 0 . 5, 5 and 50 mM by CoCl2 treatment but the metabolism of 5 and 50 mM DMN to methanol was affected less. 4. CoCl2 had little effect on MAO activities in whole homogenates, but microsomal MAO activities were markedly inhibited. 5. The inhibition of microsomal MAO indicates that CoCl2 is not a specific inhibitor of cytochrome P-450-dependent biotransformations and consequently the inhibition of DMN metabolism is not evidence of a wholly cytochrome P-450-dependent process.

Animals↗
PubMed1982

Studies on the metabolism of dimethylnitrosamine in vitro by rat-liver preparations. I. Comparison with mixed-function oxidase enzymes.

1. The metabolism of dimethylnitrosamine (DMN) to formaldehyde by rat-liver preparations has been studied at substrate concn. of 0.5, 5 and 50 mM and compared with mixed-function oxidase enzyme activities. 2. The microsomal metabolism of low (0.5 and 5 mM) and high (50 mM) substrate concn. of DMN was differentially affected by acetone addition or KI treatment. 3. A series of heterocyclic compounds related to pyrazole were potent inhibitors of metabolism of 0.5 and 5 mM DMN at concn. which had little effect on mixed-function oxidase activities. In contrast, purine addition slightly stimulated the metabolism of low but not high concn. of DMN. 4. The results are consistent with the suggestion that multiple enzymic pathway(s) are involved in hepatic DMN metabolism and that some of these pathway(s) may be independent of cytochrome P-450.

Acetone↗
PubMed1982

The route and significance of endogenous synthesis of alkaloids in animals.

There is now substantial evidence that several TIQs and beta-carbolines are present in vivo and increase during certain pathological conditions. It still remains to be determined, however, precisely what roles they play in endogenous functions and whether or not they are critical for the expression of these pathological conditions. Accumulating biochemical information continues to support the notion that these compounds can act as false transmitters. The exciting new findings, which will certainly receive a great deal more attention, concern the interaction of some of the beta-carbolines with the benzodiazepine receptor. Determining if a beta-carboline is an endogenous receptor ligand will attract further research interest on the theoretical and specifically clinically-directed levels. Biochemical, morphological, and behavioral data indicate that some of the condensation products can act as neurotoxins. Very few experiments have included an examination of long-term effects of exposure to one of these alkaloids, so the amount of information on this issue is limited. Chronic rather than acute administration of an alkaloid is more likely to mimic the pathological states in which these compounds are hypothesized to play a role. Biochemically, both the dopaminergic and serotonergic systems have been shown to be affected by chronic treatments with certain alkaloids. Progressive and long-term behavioral alterations also have been reported. Such changes may reflect an adaptation to an increase or decrease in activity of particular systems or a neurotoxic action.

Alcoholism↗
PubMed1981

Tetrahydroisoquinolines (TIQs) do not act on opiate receptors in the guinea-pig ileum.

The myenteric plexus-longitudinal muscle preparation of the guinea-pig ileum was stimulated with supra-maximal electrical field stimulation at 0.1 Hz. The contractile response was inhibited by salsolinol (1-300 microM) and tetrahydropapaveroline (THP) (3-30 micro M) but not by (cis)-3-carboxysalsolinol. S(-)-Salsolinol was more potent than R(+)-salsolinol. The inhibition by salsolinol and THP was unchanged by naloxone (up to 10 micro M). However, naloxone completely prevented the inhibition induced by normorphine, with a pA2 of 8.66. The results indicate that salsolinol and THP do not interact with opiate receptors in this preparation.

Acetylcholine↗