Investigations of mechanisms of reactive metabolite formation from (R)-(+)-pulegone

Nelson, Sidney D.; McClanahan, Robert H.; Thomassen, David G.; Gordon, W. Perry; Knebel, Norbert

doi:10.3109/00498259209051869

Cited by 33 publications

(25 citation statements)

References 16 publications

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“…A dose-response study showed that deuterium substitution for hydrogen in the allylic methyl groups decreased the extent of hepatocellular injury in mice by 2-to 3-fold (Gordon et al, 1987). An intrinsic deuterium isotope effect was observed in vitro for oxidation (k H /k D ϳ7-8) of the allylic methyl groups of pulegone to an E-allylic alcohol and menthofuran, which arises from intramolecular cyclization of a Z-allylic alcohol and subsequent dehydration (Table 4 from Nelson et al, 1992). Isotopically sensitive branching of the metabolism of pulegone to other oxidation products also occurs (Nelson et al, 1992).…”

Section: Use Of Deuterium Isotope Effects To Probe P450 Reactionsmentioning

confidence: 99%

“…An intrinsic deuterium isotope effect was observed in vitro for oxidation (k H /k D ϳ7-8) of the allylic methyl groups of pulegone to an E-allylic alcohol and menthofuran, which arises from intramolecular cyclization of a Z-allylic alcohol and subsequent dehydration (Table 4 from Nelson et al, 1992). Isotopically sensitive branching of the metabolism of pulegone to other oxidation products also occurs (Nelson et al, 1992). The relatively low isotope effect observed for pulegone-d 3 appears to reflect the ability of the isopropylidene group to topomerize within the cytochrome P450 active site after initial hydrogen atom abstraction (McClanahan et al, 1988).…”

Section: Use Of Deuterium Isotope Effects To Probe P450 Reactionsmentioning

confidence: 99%

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The Use of Deuterium Isotope Effects to Probe the Active Site Properties, Mechanism of Cytochrome P450-Catalyzed Reactions, and Mechanisms of Metabolically Dependent Toxicity

Nelson¹,

Trager²

2003

Drug Metab Dispos

141

121

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Critical elements from studies that have led to our current understanding of the factors that cause the observed primary deuterium isotope effect, (k H /k D )obs, of most enzymatically mediated reactions to be much smaller than the "true" or intrinsic primary deuterium isotope effect, k H /k D , for the reaction are presented. This new understanding has provided a unique and powerful tool for probing the catalytic and active site properties of enzymes, particularly the cytochromes P450 (P450). Examples are presented that illustrate how the technique has been used to determine k H /k D , and properties such as the catalytic nature of the reactive oxenoid intermediate, prochiral selectivity, the chemical and enzymatic mechanisms of cytochrome P450-catalyzed reactions, and the relative active site size of different P450 isoforms. Examples are also presented of how deuterium isotope effects have been used to probe mechanisms of the formation of reactive metabolites that can cause toxic effects.Historically, the determination of deuterium isotope effects has been a powerful tool to help unravel the intricacies of carbon-hydrogen bond cleavage and define the mechanism of specific chemical reactions. The intrinsic primary isotope effect, k H /k D , for a reaction is the magnitude of the isotope effect on the rate constant for the bond-breaking step (C-H versus C-D) of the reaction and is related to the symmetry of the transition state for that step. The larger the isotope effect, the more symmetrical the transition state, with the theoretical limit being 9 at 37°C in the absence of tunneling effects (Bell, 1974). The chemical events leading to the transition state and subsequent formation of products are the descriptors of a chemical mechanism. It is the relationship of k H /k D to transition state that provides mechanistic insight. Thus, k H /k D is the quantity that needs to be known, and for homogenous chemical reactions, the experimentally observed deuterium isotope effect, (k H /k D )obs, where (k H /k D )obs is defined as the ratio of a kinetic parameter such as V max or V max /K m obtained from a nondeuterated substrate to a deuterated substrate, is identical to k H /k D . This is generally not true of enzymatically mediated reactions and is the reason for the much less successful application of deuterium isotope effects to such reactions until the system was better understood. The experimentally observed isotope effect, (k H /k D )obs, was invariably found to be much smaller than k H /k D , the intrinsic isotope effect for that reaction, thereby obscuring both meaning and mechanism. Even more perplexing was the observation that (k H /k D

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Section: Use Of Deuterium Isotope Effects To Probe P450 Reactionsmentioning

confidence: 99%

Section: Use Of Deuterium Isotope Effects To Probe P450 Reactionsmentioning

confidence: 99%

The Use of Deuterium Isotope Effects to Probe the Active Site Properties, Mechanism of Cytochrome P450-Catalyzed Reactions, and Mechanisms of Metabolically Dependent Toxicity

Nelson¹,

Trager²

2003

Drug Metab Dispos

141

121

View full text Add to dashboard Cite

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“…18,19 Biosynthesis of 3 and 4 from pulegone via 11 has been shown to occur in mouse and human liver, 20,21 in which the oxidation is performed by cytochrome P-450s, as shown in Scheme 7. Considering this, we propose a similar biochemical pathway in peppermint species, where 1 would be on the pathway from 11 to 3.…”

Section: Identification Of Menthofurolactone 1 In Mintmentioning

confidence: 99%

Menthofurolactone: a new p‐menthane lactone in Mentha piperita L.: analysis, synthesis and olfactory properties

Frérot

Bagnoud

Vuilleumier

2002

Flavour & Fragrance J

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3,6-Dimethyl-4,5,6,7-tetrahydro-benzo[b]-furan-2(3H)-one (D menthofurolactone), first reported as a by-product in the oxidation of menthofuran and hitherto unknown in nature, is shown to be naturally occurring in Mentha piperita L. essential oil. In addition to a description of its synthesis and organoleptic properties, the key role of menthofurolactone in the flavour profile of peppermint oil is demonstrated by mint oil analysis and olfactory studies.

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“…The possible formation of the ketoenal via a pathway involving 2-hydroxy-(R)-(+)-menthofuran also is indicated and this compound has been isolated after incubation of (R)-(+)-menthofuran with human cytochrome P450s. Further evidence for this pathway is provided by the isolation both in vivo and in vitro of (+)-mintlactone and (-)-isomintlactone, which are rearrangement products of 2-hydroxy(R)-(+)-menthofuran (Nelson et al, 1992a;Thomassen et al,1992;Khojasteh-Bakht et al,1999).…”

Section: Hazard Identification/characterisationmentioning

confidence: 99%

Pulegone and Menthofuran in flavourings ‐ Opinion of the Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in contact with Food (AFC)

Flavourings¹

2008

EFS2

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SUMMARYThe Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food is asked to evaluate substances used as flavouring substances or present in flavourings or present in other food ingredients with flavouring properties. In particular, the Panel is asked to advise the Commission on the implications for human health of pulegone and menthofuran in the diet.The Panel noted that the Scientific Committee on Food (SCF) had expressed an opinion on pulegone and menthofuran in July, 2002 and took cognizance of the documentation used in arriving at that opinion. The Panel also considered additional data on the metabolism and toxicological properties of pulegone and on in vivo extractability of menthofuran present in chewing gum not available to the SCF.The Panel noted that the metabolism of (R)-(+)-pulegone in mice and rats occurs mainly, though not exclusively, through pathways involving (R)-(+)-menthofuran and these two substances show a qualitatively similar hepatotoxicity. The Panel therefore agreed with the SCF opinion that the evaluation of (R)-(+)-pulegone and (R)-(+)-menthofuran should be considered together.The new 95-day toxicological data on the (R)-(+)-pulegone enabled the establishment of No Observed Adverse Effect Levels (NOAELs) in rats and mice, meeting one of the requirements of the SCF opinion. However, the data as a whole are not yet sufficient for the Panel to establish a TDI for pulegone.The Panel noted that refined estimates of pulegone intake from sweets were not available. It also noted the new estimates of intakes from chewing gum are considerably higher than some of the total estimates of mean intake from sweets, chewing gums & alcoholic beverages combined in the previous SCF opinion.The Panel observed that the current maximum permitted level of pulegone in food may lead to high intakes; particularly in subjects who consume regularly mint flavoured beverages or confectionery. For example it was noted that 500 ml/day of mint flavoured beverage and 100 g/day of mint confectionery could lead to intakes of respectively 4.2 mg/kg bw and 1.2 mg/kg bw for a 30 kg child. Pulegone and MenthofuranThe EFSA Journal (2005) 298, p. 2 of 32 The Panel found the database on (R)-(+)-menthofuran inadequate to establish an ADI for this flavouring substance. Because (R)-(+)-menthofuran may be formed during metabolism of (R)-(+)-pulegone and exhibits qualitatively similar toxicity. The Panel wishes the following studies to be provided within 2-years of the publication of this opinion.

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Investigations of mechanisms of reactive metabolite formation from (R)-(+)-pulegone

Cited by 33 publications

References 16 publications

The Use of Deuterium Isotope Effects to Probe the Active Site Properties, Mechanism of Cytochrome P450-Catalyzed Reactions, and Mechanisms of Metabolically Dependent Toxicity

The Use of Deuterium Isotope Effects to Probe the Active Site Properties, Mechanism of Cytochrome P450-Catalyzed Reactions, and Mechanisms of Metabolically Dependent Toxicity

Menthofurolactone: a new p‐menthane lactone in Mentha piperita L.: analysis, synthesis and olfactory properties

Pulegone and Menthofuran in flavourings ‐ Opinion of the Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in contact with Food (AFC)

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