PMID- 38403205
OWN - NLM
STAT- MEDLINE
DCOM- 20240401
LR  - 20240401
IS  - 1879-3169 (Electronic)
IS  - 0378-4274 (Linking)
VI  - 394
DP  - 2024 Apr
TI  - Dimethylmonothioarsinic acid (DMMTA(V)) differentially modulates the expression 
      of AHR-regulated cytochrome P450 1A enzymes in vivo and in vitro.
PG  - 32-45
LID - S0378-4274(24)00033-X [pii]
LID - 10.1016/j.toxlet.2024.02.007 [doi]
AB  - Dimethylmonothioarsinic acid (DMMTA(V)), a pentavalent thio-arsenic derivative, 
      has been found in bodily fluids and tissues including urine, liver, kidney 
      homogenates, plasma, and red blood cells. Although DMMTA(V) is a minor metabolite 
      in humans and animals, its substantial toxicity raises concerns about potential 
      carcinogenic effects. This toxicity could be attributed to arsenicals' ability to 
      regulate cytochrome P450 1 A (CYP1A) enzymes, pivotal in procarcinogen activation 
      or detoxification. The current study investigates DMMTA(V)'s impact on CYP1A1/2 
      expression, individually and in conjunction with its inducer, 
      2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). C57BL/6 mice were intraperitoneally 
      injected with 6 mg/kg DMMTA(V), alone or with 15 mug/kg TCDD, for 6 and 24 h. 
      Similarly, Hepa-1c1c7 cells were exposed to DMMTA(V) (0.5, 1, and 2 muM) with or 
      without 1 nM TCDD for 6 and 24 h. DMMTA(V) hindered TCDD-induced elevation of 
      Cyp1a1 mRNA, both in vivo (at 6 h) and in vitro, associated with reduced CYP1A 
      regulatory element activation. Interestingly, in C57BL/6 mice, DMMTA(V) boosted 
      TCDD-induced CYP1A1/2 protein and activity, unlike Hepa-1c1c7 cells where it 
      suppressed both. DMMTA(V) co-exposure increased TCDD-induced Cyp1a2 mRNA. While 
      Cyp1a1 mRNA stability remained unchanged, DMMTA(V) negatively affected protein 
      stability, indicated by shortened half-life. Baseline levels of CYP1A1/2 mRNA, 
      protein, and catalytic activities showed no significant alterations in 
      DMMTA(V)-treated C57BL/6 mice and Hepa-1c1c7 cells. Taken together, these 
      findings indicate, for the first time, that DMMTA(V) differentially modulates the 
      TCDD-mediated induction of AHR-regulated enzymes in both liver of C57BL/6 mice 
      and murine Hepa-1c1c7 cells suggesting that thio-arsenic pentavalent metabolites 
      are extremely reactive and could play a role in the toxicity of arsenic.
CI  - Copyright (c) 2024 Elsevier B.V. All rights reserved.
FAU - El-Mahrouk, Sara R
AU  - El-Mahrouk SR
AD  - Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, 
      Alberta, Canada; Faculty of Pharmacy, Tanta University, Tanta, Gharbia, Egypt.
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 - 20240224
PL  - Netherlands
TA  - Toxicol Lett
JT  - Toxicology letters
JID - 7709027
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP1A1)
RN  - 0 (dimethylmonothioarsinic acid)
RN  - N712M78A8G (Arsenic)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - 0 (Polychlorinated Dibenzodioxins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Aryl Hydrocarbon)
RN  - AJ2HL7EU8K (Cacodylic Acid)
SB  - IM
MH  - Humans
MH  - Animals
MH  - Mice
MH  - Cytochrome P-450 CYP1A1/metabolism
MH  - *Arsenic
MH  - Mice, Inbred C57BL
MH  - Cytochrome P-450 Enzyme System
MH  - *Polychlorinated Dibenzodioxins/toxicity
MH  - RNA, Messenger/genetics/metabolism
MH  - Receptors, Aryl Hydrocarbon/metabolism
MH  - Cacodylic Acid/*analogs & derivatives
OTO - NOTNLM
OT  - AHR
OT  - Arsenic
OT  - CYP1A1/2
OT  - DMMTA(V)
OT  - Dimethylmonothioarsinic acid
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- 2024/02/26 00:42
MHDA- 2024/04/01 06:43
CRDT- 2024/02/25 19:18
PHST- 2023/11/29 00:00 [received]
PHST- 2024/02/07 00:00 [revised]
PHST- 2024/02/21 00:00 [accepted]
PHST- 2024/04/01 06:43 [medline]
PHST- 2024/02/26 00:42 [pubmed]
PHST- 2024/02/25 19:18 [entrez]
AID - S0378-4274(24)00033-X [pii]
AID - 10.1016/j.toxlet.2024.02.007 [doi]
PST - ppublish
SO  - Toxicol Lett. 2024 Apr;394:32-45. doi: 10.1016/j.toxlet.2024.02.007. Epub 2024 
      Feb 24.