Nuclear Receptors

Making Mice Sensitive to Human to Xenobiotic Substrates

Science's STKE  01 Aug 2000:
Vol. 2000, Issue 43, pp. tw3
DOI: 10.1126/stke.2000.43.tw3

Endogenous steroids and many therapeutically useful drugs are metabolized by cytochrome CYP3A gene products in the liver. This represents a major source of drug interactions. Each species of mammals responds to a specific subset of lipophilic compounds (called inducers) by increased expression of the CYP3A genes; thus, drug interactions are often not detected until a drug reaches human clinical trials. Xie et al. created knockout mice for the pregnenolone X receptor (PXR). They show that these mice no longer respond to rodent-specific CYP3A inducers. Rat hepatocytes transfected with the human steroid and xenobiotic receptor (SXR) responded to chemicals that normally induce the CYP3A genes in humans. Using the PXR knockout mice, the authors created transgenic mice that express SXR. These mice now respond to inducers that cause increased expression in humans of CYP3A genes, which makes them an excellent model system in which to test drugs that may generate serious drug interactions in humans.

Xie, W., Barwick, J.L., Downes, M., Blumberg, B., Simon, C.M., Nelson, M.C., Neuschwander-Tetri, B.A., Brunt, E.M., Guzelian, P.S., and Evans, R.M. (2000) Humanized xenobiotic response in mice expressing nuclear receptor SXR. Nature 406: 435-439. [Online Journal]