Role of Constitutive Androstane Receptor (CAR) and CYP2B6 in Cyclophosphamide (CPA) Therapeutic Efficacy and Toxicity
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Abstract
Cyclophosphamide (CPA) belongs to a class of bi-functional alkylating agents called oxazaphosphorines; which have been investigated for their anti-cancer and immune-modulating effects. CPA is an integral component of several multidrug chemotherapeutic regimens that have been extensively used for the treatment of solid cancer and different types of hematopoietic malignancies. CPA was designed as a prodrug that needs to undergo cytochrome P450 (CYP) mediated hepatic oxidation to form a pharmacologically active metabolite, 4-hydroxy-CPA (4-OH-CPA), which ultimately leads to the formation of an alkylating phosphoramide mustard. Hence, the bioactivation of CPA is a crucial step for CPA to exert its cytotoxic effect that results in programmed cell death. Among others, CYP2B6 is the key enzyme primarily responsible for metabolism of CPA to 4-OH-CPA. Previous evidence indicates that constitutive androstane receptor (CAR, NR1I3) transcriptionally regulates hepatic CYP2B6 expression. To date, CITCO (6-4-chlorophenyl) imidazo[2.1-b]thiazole-5-carbaldehyde-O-(3,4dichlorobenzyl)oxime), represents the most selective and potent human CAR agonist which can robustly induce hepatic CYP2B6 expression. Nevertheless, whether CITCO could be developed into a clinically useful co-treatment agent for CPA remains unknown; and the pharmacokinetic profile and toxicological property of CITCO are largely unexplored. CPA has been known to cause major gastrointestinal side effects. Moreover, it has been widely reported that the intestinal expression of CYP2B6 is significantly higher in the small intestine compared to the liver. However, the association between an enhanced intestinal CYP2B6 expression and the intestinal toxicity caused by CPA has not been previously investigated. Since oral administration of CPA is a common practice in the clinic it would be relevant to establish the role of enhanced intestinal CYP2B6 expression towards the toxicity caused by CPA The overall goal of this project is to evaluate the potential of CITCO as an adjuvant drug candidate for CPA based chemotherapeutics by shedding light on its various in vivo traits such as systemic exposure, acute toxicity, and metabolic profile. Furthermore, this project attempts to examine the significance of intestinal CYP2B6 towards the intestinal toxicity commonly linked with the use of CPA.