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Toxicol Appl Pharmacol. 2017 Jul 1;326:54-65. doi: 10.1016/j.taap.2017.04.020. Epub 2017 Apr 20.

Toxicological characterisation of two novel selective aryl hydrocarbon receptor modulators in Sprague-Dawley rats.

Author information

1
Department of Food Hygiene and Environmental Health, Faculty of Veterinary Medicine, University of Helsinki, Finland. Electronic address: selma.mahiout@helsinki.fi.
2
Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, University of Helsinki, Finland.
3
Instituto de Bioingeniería, Universidad Miguel Hernández de Elche, Elche, Alicante, Spain.
4
Central Laboratory of the Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Finland.
5
Immunahr AB, Lund, Sweden.
6
Institute of Environmental Medicine (IMM), Karolinska Institutet, Stockholm, Sweden.
7
Department of Food Hygiene and Environmental Health, Faculty of Veterinary Medicine, University of Helsinki, Finland.

Abstract

The aryl hydrocarbon receptor (AHR) mediates the toxicity of dioxins, but also plays important physiological roles. Selective AHR modulators, which elicit some effects imparted by this receptor without causing the marked toxicity of dioxins, are presently under intense scrutiny. Two novel such compounds are IMA-08401 (N-acetyl-N-phenyl-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide) and IMA-07101 (N-acetyl-N-(4-trifluoromethylphenyl)-4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide). They represent, as diacetyl prodrugs, AHR-active metabolites of the drug compounds laquinimod and tasquinimod, respectively, which are intended for the treatment of autoimmune diseases and cancer. Here, we toxicologically assessed the novel compounds in Sprague-Dawley rats, after a single dose (8.75-92.5mg/kg) and 5-day repeated dosing at the highest doses achievable (IMA-08401: 100mg/kg/day; and IMA-07101: 75mg/kg/day). There were no overt clinical signs of toxicity, but body weight gain was marginally retarded, and the treatments induced minimal hepatic extramedullary haematopoiesis. Further, both the absolute and relative weights of the thymus were significantly decreased. Cyp1a1 gene expression was substantially increased in all tissues examined. The hepatic induction profile of other AHR battery genes was distinct from that caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The only marked alterations in serum clinical chemistry variables were a reduction in triglycerides and an increase in 3-hydroxybutyrate. Liver and kidney retinol and retinyl palmitate concentrations were affected largely in the same manner as reported for TCDD. In vitro, the novel compounds activated CYP1A1 effectively in H4IIE cells. Altogether, these novel compounds appear to act as potent activators of the AHR, but lack some major characteristic toxicities of dioxins. They therefore represent promising new selective AHR modulators.

KEYWORDS:

AH-receptor; Ima-07101; Ima-08401; Selective modulators; TCDD; Toxicity

PMID:
28433708
DOI:
10.1016/j.taap.2017.04.020
[Indexed for MEDLINE]

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