ABCB1 and ABCC1 expression in peripheral mononuclear cells is influenced by gene polymorphisms and atorvastatin treatment.
This study investigated the effects of atorvastatin on ABCB1 and ABCC1 mRNA expression on peripheral blood mononuclear cells (PBMC) and their relationship with gene polymorphisms and lowering-cholesterol response. One hundred and thirty-six individuals with hypercholesterolemia were selected and treated with atorvastatin (10 mg/day/4 weeks). Blood samples were collected for serum lipids and apolipoproteins measurements and DNA and RNA extraction. ABCB1 (C3435T and G2677T/A) and ABCC1 (G2012T) gene polymorphisms were identified by polymerase chain reaction-restriction (PCR)-RFLP and mRNA expression was measured in peripheral blood mononuclear cells by singleplex real-time PCR. ABCB1 polymorphisms were associated with risk for coronary artery disease (CAD) (p<0.05). After atorvastatin treatment, both ABCB1 and ABCC1 genes showed 50% reduction of the mRNA expression (p<0.05). Reduction of ABCB1 expression was associated with ABCB1 G2677T/A polymorphism (p=0.039). Basal ABCB1 mRNA in the lower quartile (<0.024) was associated with lower reduction rate of serum low-density lipoprotein (LDL) cholesterol (33.4+/-12.4%) and apolipoprotein B (apoB) (17.0+/-31.3%) when compared with the higher quartile (>0.085: LDL-c=40.3+/-14.3%; apoB=32.5+/-10.7%; p<0.05). ABCB1 substrates or inhibitors did not affect the baseline expression, while ABCB1 inhibitors reversed the effects of atorvastatin on both ABCB1 and ABCC1 transporters. In conclusion, ABCB1 and ABCC1 mRNA levels in PBMC are modulated by atorvastatin and ABCB1 G2677T/A polymorphism and ABCB1 baseline expression is related to differences in serum LDL cholesterol and apoB in response to atorvastatin.
Rebecchi
Ivanise Marina Moretti
IM
Faculty of Pharmaceutical Sciences, University of Sao Paulo, and University Hospital, Sao Paulo, Brazil. rebecchi@usp.br
Rodrigues
Alice Cristina
AC
Arazi
Simone Sorkin
SS
Genvigir
Fabiana Dalla Vecchia
FD
Willrich
Maria Alice Vieira
MA
Hirata
Mario Hiroyuki
MH
Soares
Sarah Aparecida
SA
Bertolami
Marcelo Chiara
MC
Faludi
André Arpad
AA
Bernik
Márcia Martins Silveira
MM
Dorea
Egidio Lima
EL
Dagli
Maria Lucia Zaidan
ML
Avanzo
José Luis
JL
Hirata
Rosario Dominguez Crespo
RD
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D000924:Anticholesteremic Agents / Q000494:pharmacology; D000069059:Atorvastatin; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000187:drug effects / Q000235:genetics*; D011758:Pyrroles / Q000494:pharmacology*
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000924:Anticholesteremic Agents; D000069059:Atorvastatin; D006538:Heptanoic Acids; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011758:Pyrroles; C513055:ABCB1 protein, human; C421109:multidrug resistance-associated protein 1