4-chlorotoluene

Specific investigations: other studies

Administrative data

Endpoint:

biochemical or cellular interactions

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: abstract only: no details available

Data source

Reference

Reference Type:

publication

Title:

Effect of p-chlorotoluene and its metabolites on rat hepatic and pulmonary cytochtome P4502B1 activity

Author:

Potocki B, Schatz R

Year:

1996

Bibliographic source:

The Toxicologist 30(1), 368 (abstract).

Materials and methods

Principles of method if other than guideline:

p-Chlorotoluene (PCT) is a volatile organic solvent. Discrepancies between observed effects on cytochrome P450 activity/content have been observed depending on whether rat Iiver and lung microsomes are exposed to PCT in vitro or in vivo. We investigated the possibility that the metabohtes of PCT may be responsible for these differences. ln the preliminary experiments, concentrations of PCT and Its Phase I metabolites which caused 50% inhibition in CYP2B activity (IC50) were studied. Hepatic and pulmonary CYP2B activity was measured through the O-dealkylation
of benzyloxyresorufin (BROD) following 15-minute in vitro incubations with PCT or its metabolites, p-chlorobenzylalcohol, p-chlorobenzylaldehyde,
and p-chlorobenzoic acid.

GLP compliance:

no

Type of method:

in vitro

Test material

Test material information

Constituent 1

Reference substance name:

4-chlorotoluene

EC Number:

203-397-0

EC Name:

4-chlorotoluene

Cas Number:

106-43-4

Molecular formula:

C7H7Cl

IUPAC Name:

4-chlorotoluene

Details on test material:

p-chlorotoluene

Test animals

Species:

other: not applicable - in vitro test

Strain:

other: not applicable - in vitro test

Sex:

not specified

Administration / exposure

Route of administration:

other: not applicable - in vitro test

Vehicle:

other: not applicable - in vitro test

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

not applicable - in vitro test

Frequency of treatment:

not applicable - in vitro test

Post exposure period:

not applicable - in vitro test

No. of animals per sex per dose:

not applicable - in vitro test

Results and discussion

Details on results:

p-Chlorobenzoic acid did not inhibit BROD activity, therefore, was not further investigated. p-Chlorobenzylalcohol only produced linear inhibition in the lung, but not in the Iiver. In subsequent experiments, hepatic and pulmonary IC50 were used for PCT and p-chlorobenzylaldehyde. Enzyme kinetic analyses (i.e., Eadie-Hofstee or Lineweaver-Burke plots) were used to characterize the type of inhibition observed. In the Iiver, uncompetitive inhibition was observed with PCT and p-chlorobenzylaldehyde. In the lung, noncompetitive inhibition was observed with PCT. pChlorobenzylalcohol
produced uncompetitive inhibition in the lung while p-chlorobenzylaldehyde behaved primarily as a noncompetitive inhibitor. The kinetic analyses therefore suggest that PCT and its two Phase I metabolites have potent inhibitory effects on BROD activity in the lung and to a lesser extent in the Iiver. This enzymatic inhibition may in part be the result of microsomal metabolism of PCT.

Any other information on results incl. tables

no further data

Applicant's summary and conclusion

Executive summary:

Discrepancies between observed effects on cytochrome P450 activity/content have been observed depending on whether rat Iiver and lung microsomes are exposed to PCT in vitro or in vivo. The possibility was investigated that the metabohtes of PCT may be responsible for these differences. ln the preliminary experiments, concentrations of PCT and Its Phase I metabolites which caused 50% inhibition in CYP2B activity (IC50) were studied. Hepatic and pulmonary CYP2B activity was measured through the O-dealkylation of benzyloxyresorufin (BROD) following 15-minute in vitro incubations with PCT or its metabolites, p-chlorobenzylalcohol, p-chlorobenzylaldehyde, and p-chlorobenzoic acid.

The inhibition of CYP2B activity by p-chlorotoluene (PCT) and its Phase I metabolites was measured through the
O-dealkylation of benzoyloxyresorufin (BROD). The enzyme kinetic analyses suggest that PCT and its Phase I
metabolites have potent inhibitory effects on BROD activity in the lung and to a lesser extent in the liver.