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,25-Dihydroxyvitamin D3
Department of Internal Medicine, University of Michigan Medical
Center, Ann Arbor, Michigan 48109 (P.S.-R., K.S.L., P.B.W.), and
Department of Pharmaceutics, University of Washington, Seattle,
Washington 98195 (K.E.T., J.M.F., M.F.P.)
The human colon carcinoma cell line, Caco-2, is widely used as a model
for oral absorption of xenobiotics. The usefulness of Caco-2 cells has
been limited, however, because they do not express appreciable
quantities of CYP3A4, the principle cytochrome P450 present in human
small bowel epithelial cells. We report that treatment of Caco-2 cells
with 1
,25-dihydroxyvitamin D3, beginning at confluence,
results in a dose- and duration-dependent increase in CYP3A4 mRNA and
protein, with little apparent effect on the expression of CYP3A5 or
CYP3A7. This treatment also results in increases in NADPH cytochrome
P450 reductase and P-glycoprotein (the MDR1 gene product)
but has no detectable effect on expression of CYP1A1, CYP2D6,
cytochrome b5, liver or intestinal fatty
acid binding proteins, or villin. Maximal expression of CYP3A4 requires an extracellular matrix on a permeable support and the presence of
serum. In the treated cells, the intrinsic formation clearance of
1
-hydroxymidazolam (a reaction characteristically catalyzed by CYP3A
enzymes) was estimated to be somewhat lower than that of human jejunal
mucosa (1.14 and 3.67 ml/min/g of cells, respectively). The
1-OH-midazolam/4-OH-midazolam product ratio produced by the cells
(~5.3) is comparable to, but somewhat lower than, that observed in
human jejunal microsomes (7.4-15.4), which may reflect the presence of
CYP3A7 in the Caco-2 cells. 25-Hydroxyvitamin D3 is less
efficacious but reproduces the effects of the dihydroxy compound, whereas unhydroxylated vitamin D is without appreciable effect. These
observations, together with the time course of response, suggest that
the vitamin D receptor may be involved in CYP3A4 regulation. The
culture model we describe should prove useful in defining the role of
CYP3A4 in limiting the oral bioavailability of many xenobiotics.
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