Arsenic trioxide (ATO) up-regulates cytochrome P450 1A (CYP1A) enzymes in murine hepatoma Hepa-1c1c7 cell line

Arsenic trioxide (ATO) is a highly toxic arsenical which has been successfully exploited for treating acute promyelocytic leukemia (APL). Unfortunately, its therapeutic efficacy is accompanied by serious toxicities with undeciphered mechanisms. Cytochrome P450 1A (CYP1A) enzymes undergo modulation by arsenicals, with ensuing critical consequences regarding drug clearance or procarcinogen activation. Here, we investigated the potential of ATO to alter basal and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced CYP1A1/1A2 expressions. Mouse-derived hepatoma Hepa-1c1c7 cells were exposed to 0.63, 1.25, and 2.5 & mu;M ATO with or without 1 nM TCDD. ATO increased TCDD-induced CYP1A1/1A2 mRNA, protein, and activity. Constitutively, ATO induced Cyp1a1/1a2 transcripts and CYP1A2 protein. ATO increased AHR nuclear accumulation and subsequently increased XRE-luciferase reporter activity. ATO enhanced CYP1A1 mRNA and protein stabilities. In conclusion, ATO up-regulates CYP1A in Hepa-1c1c7 cells transcriptionally, post-transcriptionally, and post-translationally. Therefore, ATO can be implicated in clearance-related interactions with CYP1A1/1A2 substrates, or in excessive activation of environmental procarcinogens.

Automated summary

Arsenic trioxide (ATO) is a highly toxic arsenical that is used to treat leukemia, but its therapeutic effects come with serious toxicities. This study investigated the effects of ATO on the expression of CYP1A1/1A2 enzymes, which are involved in drug clearance and carcinogen activation. The results showed that ATO increased the expression and activity of CYP1A1/1A2 in cells. This suggests that ATO may affect the clearance of drugs metabolized by these enzymes and activate carcinogens in the environment.