P21 (Cdc42/Rac)-activated kinase 1 (pak1) is associated with cardiotoxicity induced by antihistamines.
Astemizole, a non-sedating histamine H1receptor blocker, is widely known to cause cardiac arrhythmia, which prolongs the QT interval. However, the precise molecular mechanism involved in antihistamine-induced cardiovascular adverse effects other than hERG channel inhibition is still unclear. In this study, we used DNA microarray analysis to detect the mechanisms involved in life-threatening adverse effects caused by astemizole. Rat primary cardiomyocytes were treated with various concentrations of astemizole for 24 h and the corresponding cell lysates were analyzed using a DNA microarray. Astemizole altered the expression profiles of genes involved in calcium transport/signaling. Using qRT-PCR analysis, we demonstrated that, among those genes, p21 (Cdc42/Rac)-activated kinase 1 (pak1) mRNA was downregulated by treatment with terfenadine and astemizole. Astemizole also reduced pak1 protein levels in rat cardiomyocytes. In addition, astemizole decreased pak1 mRNA and protein levels in H9c2 cells and induced an increase in cell surface area (hypertrophy) and cytotoxicity. Fingolimod hydrochloride (FTY720), a pak1 activator, inhibited astemizole-induced hypertrophy and cytotoxicity in H9c2 cells. These results suggest that antihistamine-induced cardiac adverse effects are associated with pak1 expression and function.
Pharmacological Research Division, National Institute of Drug and Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, 363-700, Republic of Korea. actpotyjs@korea.kr.
Jaesuk
http://orcid.org/0000-0002-3093-8919
J
Yun
Pharmacological Research Division, National Institute of Drug and Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, 363-700, Republic of Korea.
So Young
SY
Kim
Pharmacological Research Division, National Institute of Drug and Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, 363-700, Republic of Korea.
Kyung Sik
KS
Yoon
Pharmacological Research Division, National Institute of Drug and Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, 363-700, Republic of Korea.
Heejung
H
Shin
Pharmacological Research Division, National Institute of Drug and Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, 363-700, Republic of Korea.
Ho-Sang
HS
Jeong
Pharmacological Research Division, National Institute of Drug and Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, 363-700, Republic of Korea.
Hyejoo
H
Chung
Pharmacological Research Division, National Institute of Drug and Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, 363-700, Republic of Korea.
Young-Hoon
YH
Kim
Pharmacological Research Division, National Institute of Drug and Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, 363-700, Republic of Korea.
Jisoon
J
Shin
Pharmacological Research Division, National Institute of Drug and Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, 363-700, Republic of Korea.
Hye Jin
HJ
Cha
Pharmacological Research Division, National Institute of Drug and Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, 363-700, Republic of Korea.
Kyoung Moon
KM
Han
Pharmacological Research Division, National Institute of Drug and Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, 363-700, Republic of Korea.
Seungha
S
Hyeon
Pharmacological Research Division, National Institute of Drug and Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, 363-700, Republic of Korea.
Tac-Hyung
TH
Lee
Pharmacological Research Division, National Institute of Drug and Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, 363-700, Republic of Korea.
Hye-Kyung
HK
Park
Pharmacological Research Division, National Institute of Drug and Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, 363-700, Republic of Korea. kimhs58@korea.kr.
Hyung Soo
HS
Kim
D000818:Animals; D066126:Cardiotoxicity / Q000201:enzymology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D006633:Histamine Antagonists / Q000737:chemistry / Q000633:toxicity*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D006633:Histamine Antagonists; C515906:Pak1 protein, rat; D054462:p21-Activated Kinases
Antihistamine; Astemizole; Cardiotoxicity; Genomics