Enzymic Oxidation α to the Acetylenic Group in the Metabolism of<i>N</i>-(5-Pyrrolidinopent-3-ynyl)- Succinimide (BL 14)<i>in vitro</i>

Lindeke, Björn; Hallström, Gösta; Anderson, Elisabet; Karlén, B

doi:10.3109/00498257809070017

Cited by 9 publications

(3 citation statements)

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“…Earlier evidence for the occurrence of microsomal hydroxylation at a carbon atom a to the acetylenic bond comes from the work of Lindeke et al (1978) with the oxotremorine analogue N-(5pyrrolidinopent-3-ynyl)succinimide and from the studies made by Sacher et al (1968) with certain propargyl-substituted insecticide synergists.…”

Section: Compoundmentioning

confidence: 99%

Metabolic activation of acetylenes. Covalent binding of [1,2-14C]octyne to protein, DNA and haem in vitro and the protective effects of certain thiol compounds

White¹,

Campbell²,

Farmer³

et al. 1984

Biochemical Journal

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[1,2-14C]Oct-l-yne was used to investigate metabolic activation of the ethynyl substituent in vitro. Activation of octyne by liver microsomal cytochrome P-450-dependent enzymes gave intermediate(s) that bound covalently to protein, DNA and to haem. The time course and extent of covalent binding of octyne to haem and to protein were similar. However, two different activating mechanisms are probably involved. Whereas covalent binding to protein or to DNA was inhibited by nucleophiles such as N-acetylcysteine, that to haem was little affected. When N-acetylcysteine was included in the reaction mixtures, two major octyne-N-acetylcysteine adducts were isolated and purified by high-pressure liquid chromatography. G.l.c.-mass spectrometry and n.m.r. suggest that these are the cis-trans isomers of S-3-oxo-oct-1-enyl-N-acetylcysteine. Oct-1-yn-3-one reacted non-enzymically with N-acetylcysteine at pH 7.4 and 37 degrees C with a t1/2 of about 6 s also to yield S-3-oxo-oct-l-enyl-N-acetylcysteine. The same product was formed when microsomal fractions were incubated with oct-1-yn-3-ol, N-acetylcysteine and NAD(P)+. Octyn-3-one did not appear to react with haem or protoporphyrin IX. 5. A mechanism for the metabolic activation of oct-1-yne is proposed, consisting in (a) microsomal hydroxylation of the carbon atom alpha to the acetylenic bond and (b) oxidation to yield octyn-3-one as the reactive species.

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Section: Compoundmentioning

confidence: 99%

Metabolic activation of acetylenes. Covalent binding of [1,2-14C]octyne to protein, DNA and haem in vitro and the protective effects of certain thiol compounds

White¹,

Campbell²,

Farmer³

et al. 1984

Biochemical Journal

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“…Clearly the structure of the compound containing the acetylenic bond is important in determining the route of metabolism, for example there is evidence that some acetylenic compounds characteristically undergo hydroxylation a to the triple bond. Examples are N-15-(Npyrrolidinyl)pent-3-ynyllsuccinimide (Lindeke et al, 1978) and pargyline (N-methyl-N-prop-2-ynylbenzenemethanamine; Diehl et al, 1976). Hydroxylation in the first example was microsomal, inducible with phenobarbitone, and inhibited by compound SKF 525A, CO and nicotinamide; metabolism before phenobarbitone induction was minimal, and it was concluded that the reaction was mediated by an inducible cytochrome P-450 system (Lindeke et al, 1978).…”

Section: Ch2coohmentioning

confidence: 99%

The metabolic oxidation of the ethynyl group in 4-ethynylbiphenyl in vitro

Wade¹,

Symons²,

Martin³

et al. 1980

Biochemical Journal

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1. The metabolism of 4-ethynylbiphenyl has been studied in vitro with subcellular fractions of normal and induced rat liver, and rat intestinal microflora (caecal contents). 2. Oxidation was NADPH-dependent, was inhibited by CO and stimulated by pretreatment with phenobarbitone or 3-methylcholanthrene. 3. Oxidation of the ethynyl group occurred in washed microsomal preparations, but not significantly in soluble fractions. Oxidation of the ethynyl group by a microsomal fraction preceded aromatic hydroxylation and no metabolites containing the intact ethynyl group were detected. 4. The major metabolite in liver fractions was biphenyl-4-ylacetic acid. This was the only product produced by a modified Udenfriend system. 5. Metabolism of 4-ethynylbiphenyl by rat caecal contents under anaerobic conditions produced very small amounts of 4-vinylbiphenyl. 6. In a modified Ames test with Salmonella typhimurium TA98, 4-ethynylbiphenyl gave a weak positive result that was doubled after 'activation' with an induced rat S9 fraction.

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“…As part of the pharmacological evaluation of some acetylenic amines related to oxotremorine,l their metabolism is being investigated. 2 The N-oxides sometimes appear as distinct metabolites3 but they are thermally unstable and we have accordingly investigated the thermal rearrangement of the model N-oxides (I) and (11), containing both a triple bond and a cyclic amine function.…”

mentioning

confidence: 99%