Effects of acid and lactone forms of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on the induction of MDR1 expression and function in LS180 cells.
In the present study, the ability of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), also known as statins, to regulate the gene expression and function of multidrug resistance protein 1 (MDR1/P-glycoprotein) and differences between their acid and lactone forms were examined in human intestinal epithelial LS180 cells. Some statins had the potential to induce the expression of mRNAs for MDR1 and/or CYP3A in either form. The change in the mRNA expression of MDR1 was accompanied by a change in the CsA-dependent intracellular accumulation of rhodamine 123. Simvastatin lactone, but not the acid form, exhibited a strong inductive effect on the mRNA expression of MDR1 and CYP3A in a dose-dependent manner. Sulforaphane significantly suppressed the expression of MDR1 and CYP3A mRNAs induced by atorvastatin lactone, lovastatin acid, and lovastatin lactone, comparable to the control level, and moderately inhibited that by cerivastatin acid, fluvastatin acid and simvastatin lactone. In the case of pitavastatin acid, sulforaphane had no significant effect on the expression of MDR1 mRNA.These results suggested that some statins could induce MDR1 and CYP3A gene expression and these inductive effects differed between the lactone and active hydroxy acid forms, and that PXR-mediated regulation was rarely associated with the mRNA inducibility by pitavastatin acid, unlike that by other statins.
Department of Clinical Pharmacokinetics, Kobe University Graduate School of Medicine, Japan.
Daisuke
D
Yamasaki
Tsutomu
T
Nakamura
Noboru
N
Okamura
Makiko
M
Kokudai
Naoki
N
Inui
Kazuhiko
K
Takeuchi
Hiroshi
H
Watanabe
Midori
M
Hirai
Katsuhiko
K
Okumura
Toshiyuki
T
Sakaeda
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism* / Q000502:physiology; D000143:Acids / Q000737:chemistry*; D002460:Cell Line; D005434:Flow Cytometry; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D007783:Lactones / Q000737:chemistry*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000143:Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007783:Lactones