The metabolism of a stable N-hydroxymethyl derivative of a N-methylamide

doi:10.1016/0024-3205(83)90204-7

Life Sciences

Volume 32, Issue 6, 7 February 1983, Pages 597-604

https://doi.org/10.1016/0024-3205(83)90204-7 Get rights and content

Abstract

N-Formylbenzamide and benzamide were characterised by high pressure liquid chromatography and mass spectrometry as products of the metabolism of N-hydroxymethylbenzamide in incubation mixtures with mouse liver preparations and isolated hepatocytes. This biotransformation occurred predominantly in 9000g and microsomal supernatant fractions and was also catalyzed by horse liver alcohol dehydrogenase fortified with NAD and could be inhibited by pyrazole. Unlike N-hydroxymethlbenzamide, which is very stable, N-formylbenzamide degraded rapidly to benzamide in buffer at pH 7.4 with a half-life of 7.8 min. The instability of N-formylbenzamide and the time course of its metabolic generation together with benzamide suggest that benzamide is a chemical breakdown product of N-formylbenzamide. N-Formylbenzamide was also tentatively identified as a urinary metabolite of N-hydroxymethylbenzamide. This is the first time that an N-hydroxymethyl compound has been shown to undergo metabolism either $in vitro$ or $in vivo$ .

References (17)

A. Gescher et al.
Life Sci.
(1980)
D.L. Cinti et al.
Biochem. Pharmacol.
(1972)
P. Farina et al.
Biochem. Pharmacol.
(1982)
T.A. Connors et al.
Biochem. Pharmacol.
(1974)
W. Muecke et al.
Pest. Biochem. Physiol.
(1976)
B. Ketterer et al.
Chem. Biol. Interactions
(1982)
D. ROSS, P.B. FARMER, A. GESCHER, J.A. HICKMAN and M.D. THREADGILL, Biochem. Pharmacol. (in...
D. Kingston
J. Clin. Path.
(1965)

There are more references available in the full text version of this article.

Cited by (5)

Unusual cytochrome P450 enzymes and reactions
2013, Journal of Biological Chemistry
Citation Excerpt :
Many examples are known of α-hydroxy heteroatom products that break down, e.g. carbinolamines, hemiacetals, and gem-halohydrins (Fig. 1B). However, some stable carbinolamines (5, 6) and hemiaminals (13) are known. In many cases, the initial products have not been observed directly, but indirect approaches have been used to demonstrate their existence, e.g. oxygenated halogen atoms (haloso compounds) (supplemental Fig. S1) (14, 15).
Cytochrome P450 enzymes primarily catalyze mixed-function oxidation reactions, plus some reductions and rearrangements of oxygenated species, e.g. prostaglandins. Most of these reactions can be rationalized in a paradigm involving Compound I, a high-valent iron-oxygen complex (FeO³⁺), to explain seemingly unusual reactions, including ring couplings, ring expansion and contraction, and fusion of substrates. Most P450s interact with flavoenzymes or iron-sulfur proteins to receive electrons from NAD(P)H. In some cases, P450s are fused to protein partners. Other P450s catalyze non-redox isomerization reactions. A number of permutations on the P450 theme reveal the diversity of cytochrome P450 form and function.
The formation and metabolism of N-hydroxymethyl compounds-III. The metabolic conversion of N-methyl and N, N-dimethylbenzamides to N-hydroxymethyl compounds
1983, Biochemical Pharmacology
The stability of metabolically-generated N-(hydroxymethyl) compounds was investigated using a series of N-methylbenzamides as model substrates. N-(Hydroxymethyl)-benzamide was characterized as a major metabolite of N-methylbenzamide in vitro, and was also identified as a urinary metabolite of N-methylbenzamide. N-(Hydroxymethyl) compounds were also found as metabolites of 4-chloro-N-methylbenzamide and 4-t-butyl-N-methylbenzamide in vitro. Thus substitution in the 4-position of the phenyl ring of derivatives of N-(hydroxymethyl)-benzamide did not affect their stability sufficiently to cause degradation to formaldehyde under the conditions used. N-(Hydroxymethyl)-N-methylbenzamide was identified as a metabolite of N, N-dimethylbenzamide in vitro. However, N-(hydroxymethyl)-N-methylbenzamide was less stable than N-(hydroxymethyl)-benzamide under alkaline conditions. Furthermore, N-(hydroxymethyl)-N-methylbenzamide, unlike N-(hydroxymethyl)-benzamide and its 4-substituted derivatives, was positive in the colorimetric assay for formaldehyde, presumably because of its degradation to produce formaldehyde. Thus substitution on the nitrogen atom which bears the methyl group in N-methylbenzamide markedly affected the stability of the N-methylol produced during oxidative metabolism. N-Formylbenzamide was identified as a metabolite of N-methylbenzamide in suspensions of mouse hepatocytes and also in vivo. The mechanism for its production probably involves the generation of N-(hydroxymethyl)-benzamide.
Late-occurring and long-circulating metabolites of GABA<inf>Aa</inf>2,3 receptor modulator AZD7325 involving metabolic cyclization and aromatization: Relevance to MIST analysis and application for patient compliance
2018, Drug Metabolism and Disposition
New metabolites of the drug 5-aminosalicylic acid. II. N-formyl-5-aminosalicylic acid
1991, Xenobiotica
The design and bioactivation of presystemically stable prodrugs
1988, Drug Metabolism Reviews

^☆: The previous publication in this series is reference No. 2.

^☆☆: Supported by a grant from the Medical Research Council. The authors thank John Lamb for the determination of mass spectra.

^★: Presented in part at the 8th European Workshop on Drug Metabolism, Liege, Belgium, September 1982.

⁴: To whom reprint requests should be addressed.

View full text

The metabolism of a stable N-hydroxymethyl derivative of a N-methylamide☆,☆☆,★

Abstract

Life Sci.

Biochem. Pharmacol.

Biochem. Pharmacol.

Biochem. Pharmacol.

Pest. Biochem. Physiol.

Chem. Biol. Interactions

J. Clin. Path.