Metabolism of derivatives of toluene. 6. Tolunitriles, benzonitrile and some related compounds

Bray, H. G.; Hybs, Z.; Thorpe, W. V.

doi:10.1042/bj0480192

Cited by 18 publications

(6 citation statements)

References 13 publications

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“…3-and 4-Hydroxylation of 2,6-dichlorobenzonitrile has now been demonstrated in vivo; hydroxylation is predominantly meta, owing to the inductive effect of the 2,6-dichloro atoms. The 2,6-dichloro substituents contribute to the rapid rate of hydroxylation of 2,6-dichlorobenzonitrile in vivo, since the slowness with which the metabolic products of benzonitrile and nitrobenzene are eliminated from the body has been attributed to difficulty associated with the hydroxylation of aromatic compounds that have meta-directing groups (Bray, Hybs & Thorpe, 1951;Smith, 1950;Smith & Williams, 1950). By analogy with chlorobenzene (Smith, Spencer & Williams, 1950) and naphthalene (Corner & Young, 1955), the possibility that hydroxylation of 2,6-dichlorobenzonitrile in vivo may involve intermediate formation of 2,6dichloro-3,4-dihydro-3,4-dihydroxybenzonitrile is attractive, since this diol might itself be formed from an epoxide precursor, which would also be expected to react with the thiol group of cysteine, glutathione or tissue proteins (Parke & Williams, 1958) to yield the two sulphur-containing acylamino acid metabolites that have been discussed.…”

Section: Discussionmentioning

confidence: 99%

“…The reaction is a minor one, and its extent depends on the nature of the substituents in the benzene nucleus. With benzonitrile and o-tolunitrile, oxidation of the aromatic nucleus is the major pathway of metabolism, but at least 10% of benzonitrile and 25% of o-tolunitrile are metabolized by hydrolysis of the cyano group to carboxyl (Bray et al 1951). Less than 2% of the sterically hindered 2,6-dichlorobenzonitrile is metabolized in vivo to 2,6-dichlorobenzamide plus 2,6-dichlorobenzoic acid.…”

Section: Discussionmentioning

confidence: 99%

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The comparative metabolism of 2,6-dichlorothiobenzamide (Prefix) and 2,6-dichlorobenzonitrile in the dog and rat

Griffiths¹,

Moss²,

Rose³

et al. 1966

Biochemical Journal

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1. A single oral dose of either [(14)C]Prefix or 2,6-dichlorobenzo[(14)C]nitrile to rats is almost entirely eliminated in 4 days: 84.8-100.5% of (14)C from [(14)C]Prefix is excreted, 67.3-79.7% in the urine, and 85.8-97.2% of (14)C from 2,6-dichlorobenzo-[(14)C]nitrile is excreted, 72.3-80.7% in the urine. Only 0.37+/-0.03% of the dose of [(14)C]Prefix and 0.25+/-0.03% of the dose of 2,6-dichlorobenzo[(14)C]nitrile are present in the carcass plus viscera after removal of the gut. Rats do not show sex differences in the pattern of elimination of the respective metabolites of the two herbicides. The rates of elimination of (14)C from the two compounds in the 24hr. and 48hr. urines are not significantly different (P >0.05) from one another. 2. After oral administration to dogs, 85.9-106.1% of (14)C from [(14)C]Prefix is excreted, 66.6-80.9% in the urine, and 86.8-92.5% of (14)C from 2,6-dichlorobenzo[(14)C]nitrile is excreted, 60.0-70.1% in the urine. Dogs do not show sex differences in the pattern of eliminating the metabolites of either Prefix or 2,6-dichlorobenzonitrile. 3. Dogs and rats do not show species differences in the patterns of elimination of the two herbicides. 4. Prefix and 2,6-dichlorobenzonitrile are completely metabolized; unchanged Prefix and 2,6-dichlorobenzonitrile are absent from the urine and faeces, and from the carcasses when elimination is complete. In the hydrolysed urine of rats dosed with either [(14)C]Prefix or 2,6-dichlorobenzo[(14)C]nitrile, 2,6-dichloro-3-hydroxybenzonitrile accounts for approx. 42% of the (14)C, a further 10-11% is accounted for by 2,6-dichlorobenzamide, 2,6-dichlorobenzoic acid, 2,6-dichloro-3- and -4-hydroxybenzoic acid and 2,6-dichloro-4-hydroxybenzonitrile collectively, and 25-30% by six polar constituents, of which two are sulphur-containing amino acids. 5. In the unhydrolysed urines of rats dosed with either [(14)C]Prefix or 2,6-dichlorobenzo[(14)C]nitrile, there are present free 2,6-dichloro-3- and -4-hydroxybenzonitrile, their glucuronide conjugates, ester glucuronides of the principal aromatic acids that are present in the hydrolysed urines, and two sulphur-containing metabolites analogous to mercapturic acids or premercapturic acids. 6. Prefix is thus extensively transformed into 2,6-dichlorobenzonitrile: R.CS.NH(2)-->R.CN+H(2)S, where R=C(6)H(3)Cl(2). However, the competitive reaction: R.CS.NH(2)+H(2)O-->R.CO.NH(2)+H(2)S takes place to a very limited extent.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The comparative metabolism of 2,6-dichlorothiobenzamide (Prefix) and 2,6-dichlorobenzonitrile in the dog and rat

Griffiths¹,

Moss²,

Rose³

et al. 1966

Biochemical Journal

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“…It would seem that at least part of the increased excretion of glucuronic acid after administration of pentachloronitrobenzene must be due to a toxic effect such as has been observed with certain other compounds (cf. Bray, Hybs & Thorpe, 1951).…”

Section: I955 Discussionmentioning

confidence: 99%

The metabolism of pentachloronitrobenzene and 2:3:4:6-tetrachloronitrobenzene and the formation of mercapturic acids in the rabbit

Betts

James

Thorpe

1955

Biochemical Journal

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In the rabbit 2:3:5:6-tetrachloronitrobenzene is metabolized by reduction of the nitro group, hydroxylation and mercapturic acid formation (Bray, Hybs, James & Thorpe, 1953). The last reaction is of particular interest since it is accompanied by loss of a nitro group directly attached to the benzene ring. Two further examples of this type of reaction were encountered when pentachloronitrobenzene and 2:3:4:6-tetrachloronitrobenzene were given to rabbits (Betts, James & Thorpe, 1953). A more detailed study of the metabolism of these two compounds is now reported. The stability of the nitro group in pentachloro-, the tetrachloro-and three trichloro-nitrobenzenes has been examined in relation to formation of mercapturic acids from the highly chlorinated nitrobenzenes. METHODS Melting points are uncorrected. Materials. Pentachloronitrobenzene, m.p. 1460, was supplied by Bayer Agriculture Ltd. and Hickson and Welch Ltd. and 2:3:5:6-tetrachloronitrobenzene, m.p. 990, by Bayer Agriculture Ltd. 2:3:4:6-Tetrachloronitrobenzene, m.p. 410, was prepared from 2:4:6-trichloroaniline, which was converted by a Sandmeyer reaction into 1:2:3:5tetrachlorobenzene; this was nitrated by refluxing for 0-5 hr. with HNO3 (sp.gr. 1-52) to give 2:3:4:6-tetrachloronitrobenzene. (Details were kindly supplied by Dr M.

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“…Because phenolic compounds are toxic, they are detoxified by glucuronidation in the liver and sulphurization in the colonic mucosa and then excreted as conjugate forms. [21][22][23] In this experiment, the most universal parameter affecting the amount of phenolic compounds was cecal pH that showed positive correlation with the amount of total phenol and total p-cresol in both the cecum and urine. Although the reduction in cecal pH was related to reduced production of phenolic compounds in the cecum, it is conceivable another factor may also be involved because a change in pH does not fully explain the reduction in phenolic compounds in the cecum and 24-h urine sample.…”

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confidence: 70%

Resistant starch reduces colonic and urinary p-cresol in rats fed a tyrosine-supplemented diet, whereas konjac mannan does not

Chen

Morioka

Nakagawa

et al. 2016

Bioscience, Biotechnology, and Biochemistry

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The effect of resistant starch (RS) and konjac mannan (KM) to maintain and improve the large intestinal environment was compared. Wistar SPF rats were fed the following diets for 4 weeks: negative control diet (C diet), tyrosine-supplemented positive control diet (T diet), and luminacoid supplemented diets containing either high-molecular konjac mannan A (KMAT diet), low-molecular konjac mannan B (KMBT diet), high-amylose cornstarch (HAST diet), or heat-moisture-treated starch (HMTST diet). The luminacoid-fed group had an increased content of short-chain fatty acids in the cecum. HAS caused a significant decrease in p-cresol content in the cecum, whereas KM did not. Urinary p-cresol was reduced in the HAST group compared with the T group, but not the KM fed groups. Deterioration in the large intestinal environment was only improved completely in the HAST and HMTST groups, suggesting that RS is considerably more effective than KM in maintaining the large intestinal environment.

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Metabolism of derivatives of toluene. 6. Tolunitriles, benzonitrile and some related compounds

Cited by 18 publications

References 13 publications

The comparative metabolism of 2,6-dichlorothiobenzamide (Prefix) and 2,6-dichlorobenzonitrile in the dog and rat

The comparative metabolism of 2,6-dichlorothiobenzamide (Prefix) and 2,6-dichlorobenzonitrile in the dog and rat

The metabolism of pentachloronitrobenzene and 2:3:4:6-tetrachloronitrobenzene and the formation of mercapturic acids in the rabbit

Resistant starch reduces colonic and urinary p-cresol in rats fed a tyrosine-supplemented diet, whereas konjac mannan does not

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