News of pharmaceutical intermediates: Introduction of Diindolylmethane powder (dim)

Article Date(s):05/12/2022 - 05/23/2031
The activation of cytochrome P450 3A4 (CYP3A4) and multidrug resistance protein 1 (MDR1) regulated by human pregnane X receptor (hPXR) plays an important role in mediating adverse drug interactions. Given the common use of natural products as part of adjunct human health behavior, there is a growing concern about natural products for their potential to induce undesired drug interactions through the activation of hPXR-regulated CYP3A4 and MDR1. Here, we studied whether 3,3′-diindolylmethane (DIM), a natural health supplement, could induce hPXR-mediated regulation of CYP3A4 and MDR1 in human hepatocytes and intestinal cells.3,3′-Diindolylmethane (DIM) is a natural health supplement and is the major active metabolite of indole-3-carbinol powder (I3C) (Anderton et al., 2004b), which is also a natural health supplement as well as a naturally-occurring compound in cruciferous vegetables (Bonnesen et al., 2001). DIM is used to treat recurrent respiratory papillomatosis (Auborn, 2002; Wiatrak, 2003). The emerging evidence from several studies indicates that DIM could be used for both the treatment and prevention of a variety of human cancers, including prostate and breast cancers (Azmi et al., 2008; Biersack and Schobert, 2012; Chen et al., 2012a). Additionally, DIM has the potential to promote the antitumor efficacy of chemotherapeutic drugs in combinatorial chemotherapies (Ahmad et al., 2013; Banerjee et al., 2009; Ichite et al., 2009). DIM was also thought to have potential benefits in treating/preventing cardiovascular diseases and metabolic disorders, including obesity and diabetes (Joshipura et al., 1999; Schulze et al., 2005). DIM, at its physiologically relevant concentrations, not only induced hPXR transactivation of CYP3A4 promoter activity but also induced gene expression of CYP3A4 and MDR1. DIM decreased intracellular accumulation of MDR1 substrate rhodamine 123, suggesting that DIM induces the functional expression of MDR1. Pharmacologic inhibition or genetic knockdown of hPXR resulted in attenuation of DIM induced CYP3A4 and MDR1 gene expression, suggesting that DIM induces CYP3A4 and MDR1 in an hPXR-dependent manner. Together, these results support our conclusion that DIM induces hPXR-regulated CYP3A4 and MDR1 gene expression. The inductive effects of DIM on CYP3A4 and MDR1 expression caution the use of DIM in conjunction with other medications metabolized and transported via CYP3A4 and MDR1, respectively.
Diindolylmethane powder can modulate the activity of xenobiotic receptors and xenobiotic receptor-mediated target gene expression (Bhuiyan et al., 2006; Le et al., 2003; Riby et al., 2000). For instance, DIM activates aryl hydrocarbon receptor (AHR)-regulated CYP1A gene expression in human and rat liver and intestine (Chen et al., 1998; Jellinck et al., 1993). Some previous studies suggested that DIM induces other CYPs such as CY2B and CYP3A in rat liver and intestine (Bonnesen et al., 2001; Jellinck et al., 1993; Leibelt et al., 2003; Renwick et al., 1999). CYP3A and CY2B are typical target genes of PXR, but it is unknown whether DIM induces CYP2B and CYP3A by activating PXR. In this study, we show that DIM, at its physiologically relevant concentrations, could activate hPXR and subsequently induce the expression of CYP3A4 and MDR1 in human hepatocytes and intestinal cells.