Regulation of Drug-metabolizing Enzymes by Xenobiotic Receptors
Drug-metabolizing enzymes (DMEs) and transporters play pivotal roles in the disposition and detoxification of numerous endogenous and xenobiotic chemicals. To accommodate chemical challenges, the expression of many DMEs and transporters are up-regulated by a group of ligand-activated transcription factors. The importance of such transcription factors in xenobiotic metabolism and clearance is best exemplified by the promiscuous xenobiotic receptors: the pregnane X receptor (PXR, NR1I2), the constitutive androstane receptor (CAR, NR1I3), and the aryl hydrocarbon receptor (AhR). Together, these receptors govern the inductive expression of a large array of target genes encoding phase I and II DMEs, and drug transporters. Moreover, these receptors also exhibit distinctive mechanisms of activation: ligand-dependent (direct) and ligand-independent (indirect) activation. Over the years, we have investigated the transcriptional regulation of CYP2B6, CYP3A4, BCRP, and SLC13A5 in human liver by different xenobiotic receptors, with CYP2B6 as a primary target used to illustrate the mechanisms and contribution of CAR and PXR in hepatic P450 induction. We have shown that in addition to CAR and PXR, other liver-enriched transcriptional factors such as HNF4α, C/EBPα, and HNF3β also contribute to the optimal transcription of CYP2B6 in the liver.
The Role of CAR in Cyclophosphamide-based Chemotherapy
Cyclophosphamide (CPA), an alkylating prodrug, has been used extensively in the treatment of hematologic malignancies, in particular, as an important component in the front-line regimens for non-Hodgkin lymphoma and chronic lymphocytic leukemia. Unfortunately, despite aggressive chemotherapy, a significant number of patients remain uncured due to development of drug resistance and/or intolerable toxicities. The need for further optimization of the current regimens is evident. We strive to improve the therapeutic efficacy of CPA-based chemotherapy by enhancing metabolic conversion of CPA to the pharmacologically active 4-hydroxylcyclophosphamide (4-OH-CPA) via CYP2B6, but not to the N-dechloroethyl-cyclophosphamide and the toxic chloroacetaldehyde by CYP3A4. Towards this end, we have shown that activation of human CAR preferentially induces the expression of hepatic CYP2B6 over CYP3A4 and increased the formation of 4-OH-CPA. We have also developed a unique human primary hepatocyte (HPH)-leukemia co-culture model and demonstrated that co-administration of CPA with a selective hCAR activator significantly enhances apoptosis in leukemia cells without increasing hepatotoxicity. Most recently, utilizing an improved multi-tissue co-culture model, we have shown the beneficial effects of including a hCAR activator in the clinically used regimen (CHOP) for lymphoma treatment. Eventually, we expect to establish hCAR as a novel therapeutic target facilitating CPA-based chemotherapy for hematopoietic malignancies.