Genetically determined differences in P-glycoprotein function: implications for disease risk.
The MDR1 gene product P-glycoprotein does not only contribute to drug resistance during chemotherapy of tumors but it is also expressed in healthy tissues with excretory function (intestine, liver and kidney). It transports a wide range of structurally unrelated compounds out of cells. Intestinal expression of this transporter has been shown to determine bioavailability of orally administered P-glycoprotein substrates such as digoxin. Recently, several mutations were found in the MDR1 gene. Subjects homozygous for the C3435T mutation (24% of Caucasians) have low intestinal P-glycoprotein levels, high plasma concentrations after oral digoxin and a reduced P-glycoprotein function in peripheral blood cells in comparison to the remainder of the population. Potential implications of this reduced mechanism of detoxification will be shown for three selected diseases: (1) association of low intestinal P-glycoprotein expression with development of inflammatory bowel disease; (2) implications for disease risk and therapeutic outcome of HIV; and (3) consequences of this mutation for renal P-glycoprotein expression and risk of renal cell carcinoma.
Fromm
Martin F
MF
Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstr. 112, 70376 Stuttgart, Germany. martin.fromm@ikp-stuttgart.de
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000378:metabolism; D019450:Genes, MDR / Q000235:genetics; D015658:HIV Infections / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism; D018570:Risk Assessment
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1