Biotransformations of R-(+)-pulegone and menthofuran invitro: Chemical basis for toxicity

Madyastha, K. M.; Raj, C. P.

doi:10.1016/s0006-291x(05)80897-6

Cited by 39 publications

(33 citation statements)

References 7 publications

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“…Several other furan-containing compounds (see Fig. 39) such as ipomeanol [266][267][268], menthofuran [269][270][271] and furosemide [272][273][274] also cause hepatic and renal necrosis in mice and humans or develop potentially lethal pulmonary lesions in rat.…”

Section: Occurrence and Frequencymentioning

confidence: 99%

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

Kalgutkar¹,

Gardner²,

Obach³

et al. 2005

CDM

568

505

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The occurrence of idiosyncratic adverse drug reactions during late clinical trials or after a drug has been released can lead to a severe restriction in its use and even in its withdrawal. Metabolic activation of relatively inert functional groups to reactive electrophilic intermediates is considered to be an obligatory event in the etiology of many drug-induced adverse reactions. Therefore, a thorough examination of the biochemical reactivity of functional groups/structural motifs in all new drug candidates is essential from a safety standpoint. A major theme attempted in this review is the comprehensive cataloging of all of the known bioactivation pathways of functional groups or structural motifs commonly utilized in drug design efforts. Potential strategies in the detection of reactive intermediates in biochemical systems are also discussed. The intention of this review is not to "black list" functional groups or to immediately discard compounds based on their potential to form reactive metabolites, but rather to serve as a resource describing the structural diversity of these functionalities as well as experimental approaches that could be taken to evaluate whether a "structural alert" in a new drug candidate undergoes bioactivation to reactive metabolites.

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Section: Occurrence and Frequencymentioning

confidence: 99%

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

Kalgutkar¹,

Gardner²,

Obach³

et al. 2005

CDM

568

505

View full text Add to dashboard Cite

show abstract

“…143,144 This metabolite was converted to 5,6,7,8-tetrahydro-4,7-dimethyl-7 H -cinnoline ( 69 ) upon inclusion of semicarbazide in rat, mouse or human liver microsomes, 140,143,144 indicating that 68 or some precursor to 68 is the protein-binding metabolite of menthofuran. 2-Hydroxymenthofuran ( 70 ) was also detected as a product of P450 catalyzed oxidation of menthofuran.…”

Section: 23-substituted Furansmentioning

confidence: 99%

Reactive Metabolites in the Biotransformation of Molecules Containing a Furan Ring

Peterson

2012

Chem. Res. Toxicol.

166

157

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Many xenobiotics containing a furan ring are toxic and/or carcinogenic. The harmful effects of these compounds require furan ring oxidation. This reaction generates an electrophilic intermediate. Depending on the furan ring substituents, the intermediate is either an epoxide or a cis-enedione with more ring substitution favoring epoxide formation. Either intermediate reacts with cellular nucleophiles such as protein or DNA to trigger toxicities. The reactivity of the metabolite determines which cellular nucleophiles are targeted. The toxicity of a particular furan is also influenced by the presence of competing metabolic pathways or efficient detoxification routes. GSH plays an important role in modulating the harmful effects of this class of compound by reacting with the reactive metabolite. However, this may not represent a detoxification step in all cases.

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“…There have been several studies of (R)-(+)-and (S)-(−)-pulegone metabolism in rats (99)(100)(101)(102)(103), ex vivo experiments with rat liver microsomes (104)(105)(106)(107) and human cytochrome P450 enzymes (108). Engel identified 2-(2-hydroxy-1-methylethyl)-5-methylcyclohexanone (8-hydroxymenthone), 3-hydroxy-3-methyl-6-(1-methylethyl)cyclohexanone (1-hydroxymenthone), 3-methyl-6-(1-ethylethyl)cyclohexanol (menthol), and E-2-(2-hydroxy-1-methylethylidene)-5-methylcyclohexanone (10-hydroxypulegone) as the four major metabolites of pulegone.…”

Section: Terpenes and Their Dispositionmentioning

confidence: 99%

Percutaneous Permeation Enhancement by Terpenes: Mechanistic View

Sapra

Jain

Tiwary

2008

AAPS J

136

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Abstract. A popular approach for improving transdermal drug delivery involves the use of penetration enhancers (sorption promoters or accelerants) which penetrate into skin to reversibly reduce the barrier resistance. The potential mechanisms of action of penetration enhancers include disruption of intercellular lipid and/or keratin domains and tight junctions. This results in enhanced drug partitioning into tissue, altered thermodynamic activity/solubility of drug etc. Synthetic chemicals (solvents, azones, pyrrolidones, surfactants etc.) generally used for this purpose are rapidly losing their value in transdermal patches due to reports of their absorption into the systemic circulation and subsequent possible toxic effect upon long term application. Terpenes are included in the list of Generally Recognized As Safe (GRAS) substances and have low irritancy potential. Their mechanism of percutaneous permeation enhancement involves increasing the solubility of drugs in skin lipids, disruption of lipid/protein organization and/or extraction of skin micro constituents that are responsible for maintenance of barrier status. Hence, they appear to offer great promise for use in transdermal formulations. This article is aimed at reviewing the mechanisms responsible for percutaneous permeation enhancement activity of terpenes, which shall foster their rational use in transdermal formulations.

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Biotransformations of R-(+)-pulegone and menthofuran invitro: Chemical basis for toxicity

Cited by 39 publications

References 7 publications

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

Reactive Metabolites in the Biotransformation of Molecules Containing a Furan Ring

Percutaneous Permeation Enhancement by Terpenes: Mechanistic View

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