PMID- 36893905 OWN - NLM STAT- MEDLINE DCOM- 20230411 LR - 20230411 IS - 1872-7786 (Electronic) IS - 0009-2797 (Linking) VI - 376 DP - 2023 May 1 TI - Modulation of cytochrome P450 1A (CYP1A) enzymes by monomethylmonothioarsonic acid (MMMTA(V)) in vivo and in vitro. PG - 110447 LID - S0009-2797(23)00114-X [pii] LID - 10.1016/j.cbi.2023.110447 [doi] AB - Inorganic arsenic (iAs) is a natural toxicant which, upon entering the biosphere, undergoes extensive biotransformation and becomes a portal for generating various organic intermediates/products. The chemical diversity of iAs-derived organoarsenicals (oAs) is accompanied by varying degree of toxicity that can be held responsible, at least partly, for the overall health outcome of the originally encountered parent inorganic molecule. Such toxicity may originate from arsenicals ability to modulate cytochrome P450 1A (CYP1A) enzymes, whose activity is critical in activating/detoxifying procarcinogens. In this study, we evaluated the effect of monomethylmonothioarsonic acid (MMMTA(V)) on CYP1A1 and CYP1A2 in absence and presence of their inducer; 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Therefore, C57BL/6 mice were intraperitoneally injected with 12.5 mg/kg MMMTA(V), with or without 15 mug/kg TCDD for 6 and 24 h. Moreover, murine Hepa-1c1c7 and human HepG2 cells were treated with MMMTA(V) (1, 5, and 10 muM), with or without 1 nM TCDD for 6 and 24 h. MMMTA(V) significantly inhibited TCDD-mediated induction of CYP1A1 mRNA, both in vivo and in vitro. This effect was attributed to decreased transcriptional activation of CYP1A regulatory element. Interestingly, MMMTA(V) significantly increased TCDD-induced CYP1A1 protein and activity in C57BL/6 mice and Hepa-1c1c7 cells, while both were significantly inhibited by MMMTA(V) treatment in HepG2 cells. CYP1A2 mRNA, protein and activity induced by TCDD were significantly increased by MMMTA(V) co-exposure. MMMTA(V) had no effect on CYP1A1 mRNA stability or protein stability and did not alter their half-lives. At basal level, only CYP1A1 mRNA was significantly decreased in MMMTA(V)-treated Hepa-1c1c7 cells. Our findings show that MMMTA(V) exposure potentiates procarcinogen-induced catalytic activity of both CYP1A1 and CYP1A2 in vivo. This effect entails excessive activation of such procarcinogens upon co-exposure, with potentially negative health-related outcomes. CI - Copyright (c) 2023 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 - 20230307 PL - Ireland TA - Chem Biol Interact JT - Chemico-biological interactions JID - 0227276 RN - EC 1.14.14.1 (Cytochrome P-450 CYP1A2) RN - EC 1.14.14.1 (Cytochrome P-450 CYP1A1) RN - 0 (monomethylmonothioarsonic acid) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - 0 (Arsenicals) RN - 0 (Polychlorinated Dibenzodioxins) RN - 0 (RNA, Messenger) RN - 0 (Receptors, Aryl Hydrocarbon) SB - IM MH - Humans MH - Animals MH - Mice MH - Cytochrome P-450 CYP1A2/metabolism MH - Cytochrome P-450 CYP1A1/genetics/metabolism MH - Mice, Inbred C57BL MH - Cytochrome P-450 Enzyme System/genetics MH - *Arsenicals/pharmacology MH - *Polychlorinated Dibenzodioxins/toxicity MH - RNA, Messenger/genetics/metabolism MH - Receptors, Aryl Hydrocarbon/metabolism OTO - NOTNLM OT - AHR OT - Arsenic OT - Arsenite OT - CYP1A1 OT - CYP1A2 OT - MMMTA(V) OT - TCDD COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/03/10 06:00 MHDA- 2023/04/11 06:41 CRDT- 2023/03/09 19:31 PHST- 2023/01/13 00:00 [received] PHST- 2023/02/20 00:00 [revised] PHST- 2023/03/06 00:00 [accepted] PHST- 2023/04/11 06:41 [medline] PHST- 2023/03/10 06:00 [pubmed] PHST- 2023/03/09 19:31 [entrez] AID - S0009-2797(23)00114-X [pii] AID - 10.1016/j.cbi.2023.110447 [doi] PST - ppublish SO - Chem Biol Interact. 2023 May 1;376:110447. doi: 10.1016/j.cbi.2023.110447. Epub 2023 Mar 7.