In this review we first
In this review, we first introduce the in vivo metabolism profile of VD3, and the mediation of Cyp3a gene transcription by PXR and CAR in humans, mice and rats. We then focus on the species-specific VDR-dependent regulation of human (CYP3A4, CYP3A5 and CYP3A7), mouse (mainly CYP3A11 and CYP3A13), and rat (mainly CYP3A1, CYP3A2 and CYP3A9) CYP3A isoforms (Table 1). In particular, these relationships and mechanisms may help us understand the intra- and inter-individual deviation of human CYP3A4 expression levels, and partly explain the important phenomena of varied oral drug bioavailability.
VD3 can be supplied by either diet or endogenous biosynthesis. 7-Dehydrocholesterol, an intermediate in cholesterol biotransformation, is converted to VD3 in the skin by exposure to ultraviolet B (UVB) in the sunlight. VD3 is then converted to 25-hydroxyvitamin D3 in the liver, by several CYP enzymes including CYP2R1, CYP27A1, CYP2D25, CYP2J2, and CYP3A4. As a major circulating form of VD3, 25-hydroxyvitamin D3 is transported to the kidney by vitamin D binding protein. In the proximal renal tubule, 25-hydroxyvitamin D3 is further catalyzed to 1,25-D3, the most active form of VD3, by CYP27B1. 1,25-D3 can be deactivated through the metabolism by CYP24A1 to 1,24,25-trihydroxyvitamin D3 or 1,23,25-trihydroxyvitamin D3 in the kidney, and is finally oxidized to calcitroic Senexin A by the same enzyme. Furthermore, CYP24A1 is also responsible for the hydroxylation of 25-hydroxyvitamin D31, 38. Recently, the functions of other CYPs (e.g., CYP11A1) in VD3 biotransformation have been identified, further enhancing our knowledge of VD3 metabolism14, 39. Besides phase I metabolism, VD3 and its metabolites also undergo phase II conjugation. For example, 1,25-D3 is able to be glucuronide-conjugated at the 25-hydroxyl position, mainly by UDP-glucuronyl transferase (UGT) 1A4 and to a less extent by UGT2B4 and UGT2B7. The conjugates are excreted with the bile into intestine, and further re-absorbed into the enterocytes. Human CYP3A4 is highly expressed in the liver and intestine, where VD3 exercises its main functions by regulating calcium absorption. Although CYP3A4 is not previously identified as the major enzyme responsible for the activation or deactivation of VD3, its catabolic activity towards VD3 and its hydroxylated metabolites has been increasingly revealed41, 42. The CYP3A4 metabolites have been previously designated as “inactive” and CYP3A4-mediated metabolic processes are regarded as “deactivation”. However, some physiological effects, especially the anti-tumor activities of CYP3A4 metabolites, support a broader view for the protective and regulatory effects of VD3 in vivo. In humans, CYP3A4 catalyzes the 24- or 25-hydroxylation of 1-hydroxyvitamin D3, the 23- or 24-hydroxylation of 1,25-D3, and the 4β-hydroxylation of 25-hydroxyvitamin D341, 43. These reactions mainly occur in the liver and/or the intestine, and the concentration of the product, 4β,25-dihydroxyvitamin D3, is equal to that of 1,25-D3 in plasma. Previous studies reported that in human hepatic and intestinal microsomes, the 23- or 24-hydroxylation rates of 1,25-D3 were highly correlated with that of midazolam 1ʹ-hydroxylation, and were significantly inhibited by ketoconazole. Therefore, long-term use of some antiepileptic drugs might cause CYP3A4 induction as well as increased turnover of systemic VD3, and the phenomenon of negative bone mineral balance. Similar effects were also observed after PXR agonist treatment on LS180 cells derived from human colon adenocarcinoma. In contrast, CYP3A4 inhibitors including chemicals and herb monomers inhibited the biotransformation of 1,25-D3 to 1,23S,25-trihydroxyvitamin D3 and 1,24R,25-trihydroxyvitamin D343, 46.
Regulatory roles of PXR and CAR on CYP3A in different species Human CYP3A4 induction by xenobiotics and hormones has been studied for many years. It is commonly believed that its regulation is involved with PXR (NR1I2), CAR (NR1I3), VDR (NR1I1), glucocorticoid receptor-α (GRα, NR3C1), hepatocyte nuclear factor-4α (HNF4α, NR2A1), HNF3γ, CCAAT/enhancer-binding protein α (C/EBPα) and C/EBPβ in the liver47, 48. Among these nuclear receptors involved, the interplay between PXR and/or CAR and CYP3A genes has been most extensively explored. The complexity of PXR- or CAR-mediated CYP3A induction lies in the broad panel of their ligands, which consist of endogenous steroids and exogenous chemicals. It is noteworthy that some ligands exhibit species selectivity, thus their affinities for the receptors vary across species. For instance, the human PXR (hPXR) agonist, rifampin (RIF), was unable to bind rat or mouse PXR18, 49. This was verified by the up-regulation of CYP3A11 expression in PXR/CAR double humanized mice after RIF treatment, while the hepatic CYP3A11 activity remained unchanged in normal mice. On the contrary, pregnenolone 16α-carbonitrile (PCN) was a selective mouse PXR (mPXR) or rat PXR (rPXR) agonist. Similar phenomena were also observed for CAR ligands. For example, 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl) oxime (CITCO) selectively bound human CAR (hCAR), while 1,4-bis[2-(3,5-dichloropyridyl-oxy-)]benzene (TCPOBOP) only activated mouse CAR (mCAR) but not hCAR.