TCDD, AHR, and Immune Regulation

Kerkvliet, Nancy I.

doi:10.1002/9781118140574.ch19

Cited by 1 publication

(1 citation statement)

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“…Less evident but still possible adverse health effects include type 2 diabetes and reproductive effects such as increased risk for infertility. In laboratory animals, characteristic adverse effects also include alterations in blood lipids and thyroid function, and immunological effects, but the epidemiological data for these effects in humans remain conflicting (Bastomsky 1977, Fletcher, et al 2005, Gorski and Rozman 1987, Kerkvliet 2011, Pohjanvirta, et al 1989, White, et al 2011. The current consensus is that the adverse effects of dioxins are a consequence of untimely and protracted activation of the AHR, while its appropriate activation is in fact fundamental for normal development and function of all vertebrates, especially for the balanced action of immune system (Bock and Köhle 2006, Denison, et al 2011, Fernandez-Salguero, et al 1995, Harrill, et al 2013.…”

Section: Discussionmentioning

confidence: 99%

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

Mahiout

Lindén

Esteban

et al. 2017

Toxicology and Applied Pharmacology

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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.

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