A paper, entitled “Mode of action and human relevance of THF-induced mouse liver tumours” published in Toxicology Letters1 presents research and results demonstrating that THF, a non-genotoxic mouse liver carcinogen that induces liver tumours in mice, likely does so via Constitutive Androstane Receptor (CAR) activation, a mechanism that has limited, if any, relevance to humans.
The research carried out at Concept Life Sciences demonstrated a CAR-mediated mode of action for THF by comparing results in Car/Pxr gene knockout mice with those obtained in normal mice.
The research was a collaboration between Concept Life Sciences and the BASF Corporation on behalf of the THF Task Force. Audrey Vardy (Lead Principal Scientist & Operations Manager), Larry Higgins (Principal Scientist), and Andrea Augello (Team leader) led from Concept Life Sciences, Dundee, with colleagues in conjunction with Christopher J. Choi from Ashland, Inc, Erik K. Rushton from LyondellBasell, and Ralph J. Parod from BASF Corporation.
Many non-genotoxic pharmaceuticals, agrochemicals and chemicals increase the incidence of rodent liver tumours during long term carcinogenicity studies. Faced with a compound that has caused (or is expected to cause) rodent tumours, it is necessary to demonstrate the relevance or irrelevance to humans to the satisfaction of regulatory bodies. The activation of nuclear receptors, including the Constitutive Androstane Receptor (CAR), is a common Mode of Action (MOA) for chemicals that cause mouse liver tumours by a non-genotoxic MOA, as typified by the rodent liver tumours caused by long term administration of phenobarbital. The MOA for phenobarbital-induced rodent liver tumour formation can be considered to be qualitatively not plausible for humans2. The published THF research demonstrated a CAR-mediated mode of action for THF by comparing results in Car/Pxr gene knockout mice with those obtained in normal mice.
THF is an important industrial chemical used in materials as diverse as spandex and skateboard wheels, manufacture of which exceeds 800,000 tons per annum. These findings support the hypothesis that THF-induced carcinogenicity in rodents is likely mediated via CAR activation, a mechanism that has limited, if any, relevance to humans.
Concept Life Sciences has industry-leading expertise in designing and running investigative preclinical studies to demonstrate a nuclear receptor-mediated mode of action, and has previously worked with and published studies on CAR and related modes of action with companies including BASF, Monsanto, Adama and Endura.
To find out more or download this paper please click on the link below:
1 Toxicology Letters 276 (2017) 138–143. Mode of action and human relevance of THF-induced mouse liver tumors
2 Critical Reviews in Toxicology 44 (2014) 64 – 82. Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity: A case study with phenobarbital as a model constitutive androstane receptor (CAR) activator