Drug Metabolism by Intestinal Microorganisms

Scheline, Ronald R.

doi:10.1002/jps.2600571202

Cited by 207 publications

(106 citation statements)

References 126 publications

(26 reference statements)

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“…DeEds, found that DOPA administration to raibbits gave rise to an increased urinary output of m-hydroxyphenylacetic acid, presumaibly by p-dehydroxylation of DOPAC brought about to a large extent by gut flora (Scheline, 1968). Although Shaw et a.…”

Section: Discussionmentioning

confidence: 98%

The metabolism of orally administered l‐DOPA in Parkinsonism

Calne

Karoum

Ruthven

et al. 1969

British J Pharmacology

137

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1. Gas-liquid chromatographic methods were used to measure urinary acidic and alcoholic metabolites of L-DOPA, which had been administered in high oral dosage to patients with postencephalitic and idiopathic Parkinsonism. 2. The output of these compounds was normal before treatment. During drug therapy, large quantities of the dopamine metabolites, homovanillic acid and dihydroxyphenylacetic acid, were excreted but traces only of 4-hydroxy-3-methoxyphenylethanol. Noradrenaline metabolites showed little change in output other than a small increase in 4-hydroxy-3-methoxymandelic acid.3. Information was obtained about a number of minor routes of degradation which might be implicated in the therapeutic action of L-DOPA. A raised output of m-hydroxyphenylacetic acid pointed to p-dehydroxylation of dihydroxyphenylacetic acid by gut flora. Evidence of transamination as a minor metabolic pathway was obtained iby finding appreciable urinary levels of 4-hydroxy-3-methoxyphenyllactic acid. A keto-acid precursor of this compound may act as competitive inhi'bitor of an enzyme active in the normal degradation route of tyrosine, p-hydroxyphenylpyruvic acid oxidase, for increased amounts of p-hydroxyphenyllactic acid, the major metalbolic derivative of p-hydroxyphenylpyruvic acid, accumulated in the urine during DOPA treatment.

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Section: Discussionmentioning

confidence: 98%

The metabolism of orally administered l‐DOPA in Parkinsonism

Calne

Karoum

Ruthven

et al. 1969

British J Pharmacology

137

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“…Its properties are summarized in Table 4. Harwood and Gibson have suggested that in Rhodopseudomonas palustris 4-hydroxybenzoyl-CoA might be directly reduced to a non-aromatic product rather than become reductively dehydroxylated to benzoyl-CoA which then becomes reduced [35] [16]. Similar enzymes must be widespread and probably all require CoA thioester formation of the aromatic acids to be dehydroxylated.…”

Section: Discussionmentioning

confidence: 99%

Enzymes of anaerobic metabolism of phenolic compounds

Brackmann

Fuchs

1993

European Journal of Biochemistry

109

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The reductive removal of aromatic hydroxyl functions plays an important role in the anaerobic metabolism of many phenolic compounds. We describe a new enzyme from a denitrifying Pseudornonas sp., 4-hydroxybenzoyl-CoA reductase (dehydroxylating), which reductively dehydroxylates 4-hydroxybenzoyl-CoA to benzoyl-CoA. The enzyme plays a role in the anaerobic degradation of phenol, 4-hydroxybenzoate, p-cresol, 4-hydroxyphenylacetateate, and other aromatic compounds of which 4-hydroxybenzoyl-CoA is an intermediate. The enzyme is therefore induced only under anoxic conditions with these aromatic substrates, but not with benzoate or under aerobic conditions. A similar enzyme which reductively dehydroxylates 3-hydroxybenzoyl-CoA is induced during anaerobic growth with 3-hydroxybenzoate. The soluble enzyme 4-hydroxybenzoyl-CoA reductase was purified. It has a molecular mass of 260 kDa and consists of three subunits of 75, 35, and 17 kDa. The subunit composition is likely to be a2b2c2. The enzyme contains 12 mol irodmol and 12 mol acid-labile sulfur/mol and exhibits a typical ultraviolethisible spectrum of an iron-sulfur protein.The reaction requires a reduced electron donor such as reduced viologen dyes; no other co-catalysts are required, the product is benzoyl-CoA and oxidized dye. The reductase is rapidly inactivated by oxygen. The inactivation by low concentrations of cyanide or azide in a pseudo-first-order time course suggests that it may contain a transition metal in an oxidation state which reacts with these ligands. 4-Hydroxybenzoyl-CoA reductase represents a type of enzyme which is common in anaerobic aromatic metabolism of phenolic compounds. A similar enzyme is demonstrated in Rhodopseudornonas palustris anaerobically grown with 4-hydroxybenzoate. The biological significance of reductive dehydroxylation of aromatics and a possible reaction mechanism similar to the Birch reduction are discussed.Aromatic compounds comprise the second largest group of natural products. Most of the naturally occurring aromatics carry one or several hydroxyl functions which are often protected against undesired oxidation and other side reactions by methyl ether formation. They are metabolized by microorganisms following two fundamentally different strategies. Under aerobic conditions aromatic compounds are transformed by monooxygenases and dioxygenases into dihydroxylated intermediates such as catechol, protocatechuate, and gentisate. These dihydroxylated compounds are suitable for an oxidative cleavage of the aromatic ring (reviewed recently by [l]).Hydroxylation and oxidative ring cleavage by oxygenases cannot exist under anoxic conditions and therefore a different strategy is required for the anaerobic aromatic metabolism (for recent reviews see 22-61). Notably, in contrast to aerobic metabolism, hydroxylated aromatics are

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“…Flavonoid metabolites are then eliminated in urine and by the biliary route (18,22,35,40). When excreted into the bile, flavonoid metabolites flow in the small intestine and reach the hindgut where they can be reabsorbed after their hydrolysis by the microflora (30).…”

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confidence: 99%

The splanchnic metabolism of flavonoids highly differed according to the nature of the compound

Crespy

Morand

Besson

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

114

101

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Crespy, Vanessa, Christine Morand, Catherine Besson, Nicole Cotelle, Hervé Vé zin, Christian Demigné , and Christian Ré mé sy. The splanchnic metabolism of flavonoids highly differed according to the nature of the compound. Am J Physiol Gastrointest Liver Physiol 284: G980-G988, 2003; 10.1152/ajpgi.00223.2002.-The absorption and splanchnic metabolism of different flavonoids (namely quercetin, kaempferol, luteolin, eriodictyol, genistein, and catechin) were investigated in rats after an in situ perfusion of jejunum plus ileum (14 nmol/min). Net transfer across the brush border ranged widely according to the perfused compound (from 78% for kaempferol to 35% for catechin). This variation seems linked to the lipophilicity of a given flavonoid rather than to its three-dimensional structure. Except for catechin, conjugated forms of perfused flavonoids were also detected in the intestinal lumen, but the extent of this secretion depended on the nature of the perfused compounds (52% for quercetin to 11% for genistein). For some of the perfused aglycones, biliary secretion was an important excretion route: 30% of the perfused dose for genistein but only 1% for catechin. Thus the splanchnic metabolism of flavonoid is controlled by several factors: 1) the efficiency of their transfer through the brush border, 2) the intensity of the intestinal secretion of conjugates toward the mucosal and serosal sides, respectively, and 3) the biliary secretion of conjugates. These data suggested that the splanchnic metabolism of perfused flavonoids depends on the nature of the compound considered, which in turn influences their availability for peripheral tissues. absorption; biliary excretion; rats FLAVONOIDS are phenolic secondary plant metabolites responsible for much of the color and flavor of plant foods. They are ubiquitous in fruits, vegetables, and beverages, with more than 4,000 chemically different flavonoids identified to date. They are assigned to different groups according on their structure: anthocyanins, flavonols, flavones, catechins, isoflavones, and flavonones (1,8,38,43). Owing to their ubiquity in plants, humans are constantly exposed to a wide variety of flavonoids. A wealth of beneficial properties has been reported: antibacterial, antioxidant, anti-inflammatory, and anticarcinogenic effects (2, 21, 29) and estrogenic effects for isoflavones (33). Understanding the absorption and metabolism of dietary flavonoids is fundamental to determining their potential biological activity.The small intestine is a crucial site for the absorption of dietary flavonoids. In this tissue, aglycones are metabolized by intestinal conjugation enzymes, and the resulting metabolites are then secreted toward the mucosal and/or serosal sides (5, 6, 10, 13, 37). Circulating forms of absorbed flavonoids have been identified as methylated and/or glucuronidated and/or sulfated metabolites (9,12,19,23,39), resulting from the conjugative activities of both liver and intestine (7). Flavonoid metabolites are then eliminated in urine and by the bili...

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Drug Metabolism by Intestinal Microorganisms

Cited by 207 publications

References 126 publications

The metabolism of orally administered l‐DOPA in Parkinsonism

The metabolism of orally administered l‐DOPA in Parkinsonism

Enzymes of anaerobic metabolism of phenolic compounds

The splanchnic metabolism of flavonoids highly differed according to the nature of the compound

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