Study on Cytochrome P-450 Dependent Retinoic Acid Metabolism and its Inhibitors As Potential Agents for Cancer Therapy

Abstract

The relative lack of clinical success with conventional anticancer agents may be due in part to the traditional concept of cancer being a biological state rather than a dynamic process. Redefining cancer as a dynamic disease commencing with carcinogenesis introduces the possibility of chemoprevention. Retinoids offer the promise of a therapeutic option based on differentiation of premalignant as well as malignant cells. Research to date has concentrated on the use of exogenous retinoids in cancer. Although this research continues with new retinoid derivatives, an alternative approach to overcoming the drawbacks associated with exogenous retinoids has been to increase the levels of endogenous retinoic acid (RA) by inhibiting the cytochrome P450- mediated catabolism of RA using a novel class of agents known as retinoic acid metabolism blocking agents (RAMBAs which increase the level of endogenous retinoic acid (RA) within the tumor cells by blocking their metabolism. This approach presents several theoretic advantages.In the present study a wide range of established P-450 inhibitors has been screened to examine their inhibitory activity on all-trans-Retinoic acid (ATRA) metabolism. Forty-one known P450 inhibitors were tested for their inhibitory activity against RA metabolism. Most of them are nitrogen-containing compounds. The results showed that among these compounds only six compounds (N-benzyl-2-phenylethanamine, itraconazole, chlorpromazine, 5-chloro-1,3-benzoxazol-2-amine, proadifen and furazolidone) showed inhibition of RA metabolism which was > 50%. Ketoconazole and liarozole were also screened as standard potent inhibitors in the same system and gave 87.5% and 89% inhibition, respectively. The results indicate that mostly azoles with substituents in positions other than the 1-position on the ring are very weak inhibitors of RA metabolism. The most effective inhibitors (ketoconazole, itraconazole, bifonazole and clotrimazole) are 1-substituted and possess relatively large aromatic groups in the molecule. 1-Substituted imidazoles bind to cytochrome P-450 with a very high affinity but substitution in the other position of the imidazole decreases the binding affinity.

All‐trans retinoic acid eluting poly(diol citrate) wafers for treatment of glioblastoma

“…In addition, they have been shown to suppress carcinogenesis in a variety of tumor types and have demonstrated success for the treatment and chemoprevention of human cancers (Freemantle, Spinella, & Dmitrovsky, 2003). Despite these encouraging results, the effects of prolonged retinoid therapy on human cancers in the clinic has been scarce and disappointing (Ahmad, 2011). It has been suggested that the therapeutic effects of retinoids such as all-trans retinoic acid (ATRA) are undermined by its rapid in vivo metabolism and catabolism by cytochrome P450 enzymes (Ahmad, 2011;Marill, Idres, Capron, Nguyen, & Chabot, 2003;Njar et al, 2006).…”

“…Despite these encouraging results, the effects of prolonged retinoid therapy on human cancers in the clinic has been scarce and disappointing (Ahmad, 2011). It has been suggested that the therapeutic effects of retinoids such as all-trans retinoic acid (ATRA) are undermined by its rapid in vivo metabolism and catabolism by cytochrome P450 enzymes (Ahmad, 2011;Marill, Idres, Capron, Nguyen, & Chabot, 2003;Njar et al, 2006). In addition, side effects constitute a limit to the chronic use of these systemic agents (Saurat, 1992).…”

Therapeutic Potential of the Inhibition of the Retinoic Acid Hydroxylases CYP26A1 and CYP26B1 by Xenobiotics

“…While there have not been clinical trials with itraconazole or voriconazole as inhibitors of RA metabolism, there are several case reports of these compounds resulting in hypervitaminosis A symptoms, particularly in patients receiving exogenous RA [144–148]. Furthermore, there is in vitro evidence of these compounds inhibiting RA metabolism, although they are not particularly potent [27, 155]. Thus, while these compounds are capable of inhibiting RA metabolism, they have not been pursued for this purpose, most likely because of their lack of specificity and their weak inhibition of CYP26A1.…”

The clinical significance of drug interactions between dermatological and psychoactive medications

“…The metabolism of retinoids by hepatic hydroxylation involves multiple CYP450 enzymes including CYP3A4 (52,53). In vitro studies have demonstrated an 85% decrease in retinoid metabolism with coadministrated chlorpromazine and 87% decrease with ketoconazole (52).…”

“…The metabolism of retinoids by hepatic hydroxylation involves multiple CYP450 enzymes including CYP3A4 (52,53). In vitro studies have demonstrated an 85% decrease in retinoid metabolism with coadministrated chlorpromazine and 87% decrease with ketoconazole (52). A more recent clinical study with 54 participants showed no clinical significance of CYP3A4 interactions with ketoconazole, simvastatin, and cyclosporine (53).…”