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Toxicological information

Basic toxicokinetics

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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

Reference
Name:
Unnamed
Type:
Constituent
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 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:
not applicable
Positive control:
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