Cytotoxicity of chloroacetanilide herbicide alachlor in HepG2 cells independent of CYP3A4 and CYP3A7.
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Miranda SR, Meyer SA
Cytotoxicity of chloroacetanilide herbicide alachlor in HepG2 cells independent of CYP3A4 and CYP3A7.
Food Chem Toxicol. 2007 May;45(5):871-7. doi: 10.1016/j.fct.2006.11.011. Epub 2006 Nov 26.
- PubMed ID
- 17207564 [ View in PubMed]
- Abstract
Alachlor is cytotoxic to human hepatoblastoma HepG2s, a cell line that expresses constitutive CYP3A7 and dexamethasone (DEX)-inducible CYP3A4 and CYP3A7. CYP3A4 catalyzes alachlor N-dealkylation to 2-chloro-N-(2,6-diethylphenyl)acetamide (CDEPA), precursor of 2,6-diethylbenzoquinoneimine, putative reactive metabolite for rat nasal carcinogenicity. We hypothesized that HepG2 alachlor cytotoxicity would be mediated by CYP3A4/7 and increased with DEX. Here, we report time-dependent alachlor cytotoxicity (EC(50) approximately 500 microM and 264+/-17 microM at 6 and 24h, respectively) as assessed by lactate dehydrogenase leakage. DEX pretreatment (25 microM, 48 h) significantly increased CYP3A7-catalyzed luciferin 6' benzylether O-debenzylation, but had no effect on alachlor toxicity. Further, CYP3A4/7 inhibitor triacetyloleandomycin did not prevent, but rather potentiated, alachlor cytotoxicity. In agreement, CDEPA was less toxic than parent alachlor. HepG2 CYP3A4 activity was unaffected by 48 h DEX pretreatment; therefore, studies were done in DPX-2 cells, a HepG2 derivative engineered to overexpress pregnane-X receptor (PXR) that exhibits rifampicin (RIF)-inducible endogenous CYP3A4. Alachlor cytotoxicity in DPX-2 cells occurred over a concentration range equivalent to that in HepG2. CYP3A4 activity of DPX-2 cells treated with RIF (10 microM, 48 h) was twice that of untreated cells, but RIF did not increase alachlor toxicity. These results demonstrate that neither CYP3A4 nor CYP3A7 initiate a pathway leading to a toxic alachlor metabolite.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Dexamethasone Cytochrome P450 3A4 Protein Humans UnknownSubstrateInhibitorInducerDetails Dexamethasone Cytochrome P450 3A7 Protein Humans UnknownSubstrateInducerDetails Dexamethasone acetate Cytochrome P450 3A4 Protein Humans UnknownSubstrateInhibitorInducerDetails Dexamethasone acetate Cytochrome P450 3A7 Protein Humans UnknownSubstrateInducerDetails