PMID- 35872050 OWN - NLM STAT- MEDLINE DCOM- 20220816 LR - 20220816 IS - 1872-7786 (Electronic) IS - 0009-2797 (Linking) VI - 364 DP - 2022 Sep 1 TI - Down-regulation of hepatic cytochromes P450 1A1 and 1A2 by arsenic trioxide (ATO) in vivo and in vitro: A role of heme oxygenase 1. PG - 110049 LID - S0009-2797(22)00254-X [pii] LID - 10.1016/j.cbi.2022.110049 [doi] AB - Arsenic trioxide (ATO) has evolved from an environmental threat to a successful therapy for acute promyelocytic leukemia (APL) and probably for solid tumors in the future. However, its efficacy comes at a cost of multi-organ toxicity whose mechanism remains unresolved. Arsenicals have been reported to modulate cytochrome P450 1A (CYP1A) enzymes, thus modifying activation/detoxification of drugs/procarcinogens. Therefore, this study aimed to investigate the possible effects of ATO on CYP1A1 and CYP1A2, in absence and presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) using in vivo and in vitro models. For this purpose, C57BL/6 mice were intraperitoneally injected with 8 mg/kg ATO with or without 15 mug/kg TCDD for 6 and 24 h. Furthermore, HepG2 cells were treated with ATO (1, 5, and 10 muM) with or without 1 nM TCDD for 6 and 24 h. ATO significantly inhibited TCDD-mediated induction of CYP1A1/1A2 mRNA, protein, and activity in both models. ATO differentially modulated CYP1A1/1A2 basal levels in vivo. We also demonstrated that ATO downregulates CYP1A through inhibiting the transcriptional activation of its regulatory element at both basal and inducible levels. Additionally, ATO significantly induced mRNA and protein of heme oxygenase 1 (HMOX1) in vivo and in vitro. In HepG2 cells, inhibition of HMOX1 by tin (IV) mesoporphyrin (IX) (SnMP) resulted in a partial restoration of the TCDD-mediated induction of CYP1A1 activity that was inhibited by ATO co-exposure. Our findings show that ATO alters both constitutive and inducible CYP1A1/1A2 expressions through transcriptional and HMOX1-mediated post-translational mechanisms. This implies the possible involvement of ATO in clearance-related consequences for the substrates of these enzymes such as drug-drug interactions or suboptimal toxicant elimination. CI - Copyright (c) 2022 Elsevier B.V. All rights reserved. FAU - El-Ghiaty, Mahmoud A AU - El-Ghiaty MA AD - Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada. FAU - Alqahtani, Mohammed A AU - Alqahtani MA AD - Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada. FAU - El-Kadi, Ayman O S AU - El-Kadi AOS AD - Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada. Electronic address: aelkadi@ualberta.ca. LA - eng PT - Journal Article DEP - 20220721 PL - Ireland TA - Chem Biol Interact JT - Chemico-biological interactions JID - 0227276 RN - 0 (Polychlorinated Dibenzodioxins) RN - 0 (RNA, Messenger) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 1.14.14.1 (Cytochrome P-450 CYP1A1) RN - EC 1.14.14.1 (Cytochrome P-450 CYP1A2) RN - EC 1.14.14.18 (Heme Oxygenase-1) RN - S7V92P67HO (Arsenic Trioxide) SB - IM MH - Animals MH - Arsenic Trioxide/pharmacology MH - *Cytochrome P-450 CYP1A1/genetics/metabolism MH - Cytochrome P-450 CYP1A2/metabolism MH - Cytochrome P-450 Enzyme System/metabolism MH - Down-Regulation MH - Heme Oxygenase-1/metabolism MH - Mice MH - Mice, Inbred C57BL MH - *Polychlorinated Dibenzodioxins/toxicity MH - RNA, Messenger OTO - NOTNLM OT - AHR OT - Arsenic trioxide OT - CYP1A1 OT - CYP1A2 OT - HMOX1 OT - TCDD EDAT- 2022/07/26 06:00 MHDA- 2022/08/17 06:00 CRDT- 2022/07/25 01:47 PHST- 2022/01/24 00:00 [received] PHST- 2022/07/03 00:00 [revised] PHST- 2022/07/13 00:00 [accepted] PHST- 2022/07/26 06:00 [pubmed] PHST- 2022/08/17 06:00 [medline] PHST- 2022/07/25 01:47 [entrez] AID - S0009-2797(22)00254-X [pii] AID - 10.1016/j.cbi.2022.110049 [doi] PST - ppublish SO - Chem Biol Interact. 2022 Sep 1;364:110049. doi: 10.1016/j.cbi.2022.110049. Epub 2022 Jul 21.