Evaluation of the inhibition of chlorophenols towards human cytochrome P450 3A4 and differences among various species.
Sci Total Environ
; 724: 138187, 2020 Jul 01.
Article
em En
| MEDLINE
| ID: mdl-32408447
ABSTRACT
Chlorophenols (CPs) are important pollutants detected frequently in the environment. This study intended to detect the inhibitory effects of fourteen CPs (2-CP, 3-CP, 4-CP, 4C2AP, 4C3MP, 2.4-DCP, 2.3.4-TCP, 2.4.5-TCP, 2.4.6-TCP, 3.4.5-TCP, 2.3.4.5-TECP, 2.3.4.6-TECP, 2.3.5.6-TECP and PCP) towards human liver cytochrome P450 3A4 (CYP3A4). Throughout the tests, testosterone was used as the probe substrate and CPs were used as inhibitors. A series of experiments (enzyme activity assays, preliminary screening tests, inhibition kinetics determination) were conducted to determine the inhibition of CPs towards human liver CYP3A4. CPs with the inhibitory effect >80% were selected for the inhibition evaluation in liver microsomes from different animal species (monkey, rat, dog, pig). The results showed that 2.3.4-TCP, 3.4.5-TCP, and 2.3.4.5-TECP inhibited the activities of CYP3A4 by 80.3%, 93.4%, 91.6%, respectively. Inhibition kinetics type were non-competitive and inhibition kinetics constant (Ki) values were 26.4 µM, 13.5 µM, and 8.8 µM for the inhibition of 2.3.4-TCP, 3.4.5-TCP, and 2.3.4.5-TECP towards human CYP3A4, respectively. Inhibition kinetics type was competitive and Ki value was 4.9 µM for the inhibition of 2.3.4-TCP towards CYP3A4 in Monkey liver microsomes (MyLMs). Inhibition kinetic types were non-competitive and Ki values were 8.1 µM and 28.7 µM for the inhibition of 3.4.5-TCP and 2.3.4.5-TECP towards CYP3A4 in MyLMs. Inhibition kinetic types were non-competitive and Ki values were 13.8 µM, 0.6 µM, and 6.1 µM for the inhibition of 2.3.4-TCP, 3.4.5-TCP, and 2.3.4.5-TECP towards CYP3A4 in Dog liver microsomes (DLMs), respectively. By comparing Ki values and inhibition kinetic types, the dog was the most suitable model to assess the inhibition of 2.3.4-TCP and 2.3.4.5-TECP towards CYP3A4, and monkey was the most suitable model to assess the inhibition of 3.4.5-TCP towards CYP3A4. In conclusion, our recent study on the inhibition of CPs towards CYP3A4 and species differences was important for further toxicological studies of CPs in human bodies.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Clorofenóis
/
Inibidores das Enzimas do Citocromo P-450
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Sci Total Environ
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
China