2-methylfuran

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Reactive metabolites from the bioactivation of toxic methylfurans

Author:

V. Ravindranath et al.

Year:

1984

Bibliographic source:

Science, Vol. 224, p. 884-6, 1984

Materials and methods

Objective of study:

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Goal: to determine whether intermediates such as unsaturated dialdehydes (which have reactive functionality) are formed from 2-methylfuran and to assess to what extend they could be involved in the covalent binding and toxicity of 2-methylfuran.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-methylfuran

EC Number:

208-594-5

EC Name:

2-methylfuran

Cas Number:

534-22-5

Molecular formula:

C5H6O

IUPAC Name:

2-methylfuran

Specific details on test material used for the study:

not available

Radiolabelling:

no

Test animals

Species:

rat

Strain:

not specified

Remarks:

liver microsomal preparations were used

Details on species / strain selection:

not applicable

Sex:

not specified

Details on test animals or test system and environmental conditions:

not applicable

Administration / exposure

Route of administration:

intraperitoneal

Details on exposure:

not applicable

Duration and frequency of treatment / exposure:

not applicable

No. of animals per sex per dose / concentration:

not applicable

Positive control reference chemical:

not applicable

Details on study design:

Experiment 1:
Rat hepatic microsomal incubations were performed in the presence and absence of NADPH, semicarbazide, and 2-methylfuran.
HPLC analyses of extracts from incubations with 2-methylfuran showed peaks corresponding to the synthetic acetylacrolein. When NADPH or semicarbazide or both were deleted, no such peaks were observed.
Subsequent preparative HPLC, purification by gel permeation chromatography and further comparisons by mass spectroscopy with acetylacrolein standards confirmed the identity. It appears that the aldehyde is the principal binding species.

Experiment 2:
To investigate the possibility that the unsaturated aldehyde might require further activation before it was bound.
Synthetic acetylacrolein was shown to be bound quickly in microsomal incubations and there was no further enhancement by the presence of NADPH.

Details on dosing and sampling:

not specified

Statistics:

not applicable

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

not applicable

Details on distribution in tissues:

not applicable

Details on excretion:

not applicable

Any other information on results incl. tables

Results experiment 1:

HPLC analyses of extracts from incubations with 2-methylfuran showed peaks corresponding to the synthetic acetylacrolein. When NADPH or semicarbazide or both were deleted, no such peaks were observed.

Subsequent preparative HPLC, purification by gel permeation chromatography and further comparisons by mass spectroscopy with acetylacrolein standards confirmed the identity. It appears that the aldehyde is the principal binding species.

Results experiment 2:

Synthetic acetylacrolein was shown to be bound quickly in microsomal incubations and there was no further enhancement by the presence of NADPH.

Applicant's summary and conclusion

Conclusions:

The unsaturated aldehyde acetylacrolein has been identified as the principal reactive intermediate of 2-methylfuran, that is produced and bound covalently to tissue macromolecules in hepatic and pulmonary microsomal systems in vitro

Executive summary:

This study investigated the mechanism of toxicity of furans after cytochrome P-450 monooxygenase-catalyzed bioactivation of the test compound in situ directly within the target tissue to highly reactive electophilic products.

The results of the study provides new insight into the metabolic activation of toxic furans. At least in the case of alkylfurans, the unsaturated aldehyde intermediates are the products of microsomal metabolism. Therefore, these reactive compounds may be the ultimate toxic metabolites responsible for target tissue alkylation and for toxicity produced by the parent furans in vivo. Epoxides, even if formed transiently, appear not to play a major role in the covalent binding nor in the toxicity of the simple furan.

HPLC analyses of extracts from incubations with 2-methylfuran showed peaks corresponding to the synthetic acetylacrolein. When NADPH or semicarbazide or both were deleted, no such peaks were observed.

Synthetic acetylacrolein was shown to be bound quickly in microsomal incubations and there was no further enhancement by the presence of NADPH.

The unsaturated aldehyde acetylacrolein has been identified as the principal reactive intermediate of 2-methylfuran, that is

produced and bound covalently to tissue macromolecules in hepatic and pulmonary microsomal systems in vitro