Ethyl-phenol metabolisms

As early as 1964 it was recognized that 4-ethyl phenol and 4-ethyl guaiacol were produced by yeast and bacteria during fermentation by the decarboxylation of the hydroxyciimamic acids p-coumaric and fendic acid (88). Later it was reported that among yeast only Brettanomyces species possess the metabolic ability to enzymatically decarboxylate hydroxycinnamic acids to produce ethyl derivatives (29, 89). Heresztyn was the first to identify 4-ethyl phenol and 4t-ethyl guaiacol as the major volatile phenolic compounds formed by Brettanomyces yeast (84). ... 

Isovaleric acid (3-methyl butanoic acid) was found to be the dominant odorant in the "high Brett" wine as detected by CharmAnalysis. The odor described by the GCO sniffer was rancid the chemical identity of the odorant was confirmed by GC-MS. This acid is produced in wine by yeast as a metabolic byproduct of protein (99). Volatile phenolic compounds, such as 4-ethyl guaiacol, guaiacol, and 4-ethyl phenol, were also among the dominate odor active compounds in this wine however, the individual contribution by each of the three phenolics was half or less than the odor activity of isovaleric acid. 

For many years (Dnbois, 1983), ethyl-phenols were thought to result from the metabolism of lactic bacteria. However, it was never possible to link their appearance to the completion of malolactic fermentation or to the storage of wines in the presence of lees containing bacteria (Di Stefano, 1985 Chatonnet et al, 1992b). 

In addition to bacteria, Brettanomyces and Dekkera contaminant yeasts, always present in wineries, may develop in new or used barrels during summer, regardless of the presence or absence of air. Their metabolism, accompanied by the production of unpleasant-smelling (Section 8.4.5) ethyl-phenols (Table 13.25), may continue in the bottle. 

Biochemically, 4-ethyl guaiacol and 4-ethyl phenol originate from ferufic acid and /vcoumaric acid, respectively. The reaction is a two-step process with an initial decarboxylation of the hydroxycinnamic acids catalyzed by cinnamate decarboxylase and the reduction of the vinyl phenol intermediates by vinyl phenol reductase (Fig. 11.1). Although the specific coenzyme involved remains unknown, one possible metabolic benefit of the second reaction to Brettanomyces could be reoxidation of NADH. Under low oxygen conditions such as those found in wines, the availability of NAD can be limited so that carbohydrate metabolism is inhibited (Section 1.5.1). Reduction of the vinyl phenols to the ethyl phenols would allow the cell to increase the availability of NAD and thus maintain metabolic functions. 

K. F. Thomsen, F. Strpm, B. V. Sforzini, M. Begtrup, N. Mprk, Evaluation of Phenyl Carbamates of Ethyl Diamines as Cyclization-Activated Prodrug Forms for Protecting Phenols against First-Pass Metabolism , Int. J. Pharm. 1994, 112, 143-152. 

Reactions of anthocyanins and flavanols take place much faster in the presence of acetaldehyde that is present in wine as a result of yeast metabolism and can also be produced through ethanol oxidation, especially in the presence of phenolic compounds, or introduced by addition of spirit in Port wine technology. The third mechanism proposed involves nucleophilic addition of the flavanol onto protonated acetaldehyde, followed by protonation and dehydration of the resulting adduct and nucleophilic addition of a second flavonoid onto the carbocation thus formed. The resulting products are anthocyanin flavanol adducts in which the flavonoid units are linked in C6 or C8 position through a methyl-methine bond, often incorrectly called ethyl-link in the literature. 

O-dealkylation. Aromatic methyl and ethyl ethers may be metabolized to give the phenol and corresponding aldehyde (Fig. 4.16), as illustrated by the de-ethylation of phenacetin (Fig. 4.20). Ethers with longer alkyl chains are less readily O-dealkylated, the preferred route being co-l-hydroxylation. 

Thomsen, K.F. Strom, F. Sforzini, B.V. Begtrup, M. Mprk, N. Evaluation of phenyl carbamates of ethyl diamines as cyclization-activated prodrug forms for protecting phenols against first-pass metabolism. Int. J. Pharma. 1994, 112, 143-152. 

Urinary phenol, cresols, /7-nitrophenol, and /7-aminophe-nol are biological indicators of human exposure to aromatic hydrocarbons. Fig. 7 illustrates the scheme of phase 1 and phase 2 metabolism of inhaled benzene and toluene vapors, while Fig. 8 shows the metabolism of inhaled xylene and ethyl benzene vapors. 

Wang (1975) determined indoor air concentrations of several bioeffluents in a mechanically ventilated 2400-m lecture theatre containing 225-389 occupants. These were [with range of average concentrations (pg/m )] ethanol (43-84), acetone (49-70), methanol (37-72), butyric acid (42-54), acetic acid (21-24), phenol (15-18), amyl alcohol (13-27), diethyl ketone (6-20), ethyl acetate (9-31), toluene (7-36), acetaldehyde (2-8) and allyl alcohol (4-9). Many of these were considered to originate from metabolic breakdown of foodstuffs or from food components. 

The structure-activity relationships of p-aminophenol derivatives have been widely studied. Based on the comparative toxicity of acetanilide and acetaminophen, aminophenols are less toxic than the corresponding aniline derivatives, although p-aminophenol itself is too toxic for therapeutic purposes. Etherification of the phenolic function with methyl or propyl groups produces derivatives with greater side effects than with ethyl groups. Substituents on the nitrogen atom that reduce basicity reduce activity unless that substituent is metabolically labile (e.g., acetyl). Amides derived from aromatic acids (e.g., N-phenylbenzamide) are less active or inactive. 

The metabolism of BaP in isolated hepatocytes from 3-methylcholanthrene-treated rats has been studied and compared to microsomal metabolism (59). After 5 minutes of metabolism, the patterns of the ethyl acetate-soluble metabolites from both systems were similar. However, with increased time the water-soluble metabolites of BaP increased. These metabolites were partially glucuronide, sulfate, and glutathione conjugates of the phenolic metabolites and BaP-4,5-epoxide. Inhibition of these conjugation reactions resulted in increased levels of binding of BaP to DNA. 

The metabolism of other closely related coumarin derivatives has also been investigated mainly in rabbits and rats by different authors [56, 57, 59, 68]. Different amounts of metabolites with intact ring systems or of open ring and other phenolic derivatives were identified when the biotransformation of 3,4-dihydrocoumarin [69], 4-methylcoumarin [70], 3,4-dihydro-6-methylcoumarin [71], and hydroxycoumarins [48, 53] were studied in rats [72] (Table 3.2). Like the major route of 7-hydroxylation of coumarin, dicoumarol (13) and tromexan (ethyl-bis-coumacetate) are also metabolised by hydroxylation in man, mostly in the 7-position (14) of one of the coumarin rings (Figure 3.4) [73, 74]. 

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