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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1999

Materials and methods

Objective of study:
metabolism
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
A study was performed to determine the P450 dependency of omega and omega-1-hydroxylation of various fatty acids, including lauric acid. The omega and omega-1-hydroxylations were determined by incubating microsomes (0.3 mg protein) in a mixture containing 100 uM fatty acid (0.5 uCi) in 0.12 M potassium phosphate with a pH of 7.4. HPLC was then used to determine the metabolites. Inhibition of the CYP2E1 enzyme by following a similar procedure, but adding 100 mM of DMSO and using 0.05 mM lauric acid. Anti-CYP2E1 and anti-CYP4A1 antibodies were also assayed.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Aldrich-Sigma

RADIOLABELLING INFORMATION (if applicable)
- Specific activity: 50 mCi/mmol
- Locations of the label:1-14C
Radiolabelling:
yes

Test animals

Species:
other: human, dog, rat, mouse, gerbil, hamster, monkey
Strain:
other: rat- SD, mouse - Swiss, hamster - mongolian, dog - beagle, monkey - cynomolgus

Administration / exposure

Statistics:
Correlation coefficients were calculated using an ANOVA table by the least-square regression analysis.

Results and discussion

Main ADME resultsopen allclose all
Type:
metabolism
Results:
Lauric acid was the most actively metabolized fatty acid regardless of species. All other fatty acids contained longer carbon chains.
Type:
metabolism
Results:
DMSO inhibited the omega-1-hydroxylation of lauric acid, but not the omega-hydroxylation of lauric acid, indicating lauric acid is metabolized by CYP2E1 by omega-1-hydroxylation.
Type:
metabolism
Results:
Anti-2E1 also significantly inhibited the omega-1-hydroxylation of lauric acid, but not the omega-hydroxylation, again indicating that lauric acid is metabolized by CYP2E1 via omega-1-hydroxylation.
Type:
metabolism
Results:
Anti-4A1 did not inhibit the omega-1-hydroxylation of lauric acid, but did significantly inhibit the omega hydroxylation of lauric acid. This indicates CYP4A1 is involved in omega-hydroxylation, but not omega-1-hydroxylation.
Type:
metabolism
Results:
omega-1-hydroxylation of lauric acid was significantly correlated with the levels of cytochrome P450 2E1 (r=0.94).
Type:
metabolism
Results:
omega-Hydroxylation of lauric acid was significantly correlated with the levels of cytochrome P450 4A1 (r=0.75).

Applicant's summary and conclusion

Executive summary:

A study was performed to determine the P450 dependency of omega and omega-1-hydroxylation of various fatty acids, including lauric acid. The omega and omega-1-hydroxylations were determined by incubating microsomes (0.3 mg protein) in a mixture containing 100 uM fatty acid (0.5 uCi) in 0.12 M potassium phosphate with a pH of 7.4. HPLC was then used to determine the metabolites. Inhibition of the CYP2E1 enzyme by following a similar procedure, but adding 100 mM of DMSO and using 0.05 mM lauric acid. Anti-CYP2E1 and anti-CYP4A1 antibodies were also assayed. Results showed that omega-1-hydroxylation of lauric acid was significantly correlated with the levels of cytochrome P450 2E1 (r=0.94), and omega-hydroxylation of lauric acid was significantly correlated with the levels of cytochrome P450 4A1 (r=0.75).