McRee R, Heintz MM, Baldwin WS. Inhibition of CYP2B6 does not necessarily alter toxicity except in the case of chemicals with known active metabolites. Abstract #1292, Society of Toxicology meeting, San Antonio, TX, March 2018.
CYP2B6, a member of the cytochrome P450 family, metabolizes many xenobiotics, including clinical drugs, environmental toxicants, and endobiotics such as testosterone and fatty acids. We used the Vivid® CYP2B6 (Life Technologies, Grand Island, NY USA) to determine potent inhibitors of CYP2B6 because these compounds have the potential to cause adverse drug reactions and alter endobiotic metabolism. CYP2B6 inhibitors with EC50s significantly lower than 1 μM include endosulfan, parathion, atrazine, and nonylphenol. Those with EC50s near 1 μM include triclosan, arachidonic acid, docosahexaenoic acid (DHA), and lithocholic acid. Several endobiotics have EC50s near 1 μM. Inhibition may perturb metabolism of other chemicals, but it does not necessarily indicate key metabolism leading to detoxification or activation. Therefore, we compared toxicity between HepG2 cells and CYP2B6-transfected HepG2 cells exposed to nonylphenol, clopidogrel, atrazine, parathion, chlorpyrifos, and triclosan as measured in 96-well plates via MTS assays. We are currently treating cells with endobiotics such as polyunsaturated fatty acids. Somewhat surprisingly the presence of CYP2B6 decreased the toxicity of parathion nearly 50% and chlorpyrifos 25% probably through increased production of 3,5,6-tricloro-2-pyridinol and p-nitrophenol, relative to chlorpyrifosoxon and paraoxon, respectively. This is interesting because the primary adverse effects of these chemicals is mediated through the nervous system. In contrast, the presence of CYP2B6 in HepG2 cells slightly increased the toxicity of atrazine (10-15%). The other chemicals were not effected by the presence of CYP2B6. In conclusion, inhibition of CYP2B6 can lead to changes in toxicity for select chemicals.