Effect of Calcium Channel Blocker on Acetaminophen-induced Hepatotoxicity in Rats and Histopathologic Examination

Acetaminophen에 의해 유도된 흰주의 간손상에 미치는 Calcium channel Blocker의 효과 및 조직학적 소견

The acetaminophen (AP AP), an antipyretic and analgesic agent, induces the hepatotoxicity by increasing influx of calcium and destabilizing the cellular membrane which can be caused by N-acetyl-p-benzoquinoneimine generated by cytochrome P-450 (CYF-450) when it is overdosed. Diltiazem (DIL), a calcium channel blocking agent, has been known to suppress the CYF-450 activities. To study the effect of DIL in APAP treated rats, the serum biotransformational enzyme analyses and the liver histopathologic examination were conducted on the rats which had been administered DIL at 3, 6, 9 and 12 hours after the 3,000 mg/kg of APAP administration. Following a single dose of DIL administered 12 hours after AP AP administration, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, malondialdehyde and calcium contents of liver and microsome were significantly reduced. Glutathione S-transferase (GST) activity was significantly increased. Histopathologic studies showed that DIL had prevented the development of centrilobular necrosis induced by AP AP in liver tissue. Our results suggested that diltiazem could inhibit the formation of free radical and the influx of calcium and could increase GST activity. Therefore, diltiazem can be administered at the time of 12 hours after overdosed AP AP to diminish the liver damage.

해혈 및 진동 효과를 가진 APAP는 과량 복용시 CYP-450에 의해 독성 유발 물질인 NAPQI로 대사되어 간장과 세포막을 붕괴시켜 세포 내 calcium 유입을 증가시킴으로서 간세포의 괴사를 일으킨다. DIL은 CYP-450 작용을 억제하는 것으로 알려진 칼슘채널차단제이다. 따라서 본 연구에서는 APAP 300mg/kg을 경구 투여한 후 3, 6. 9 및 12시간에 DIL을 복상내로 투여하여 DIL이 APAP의 독성에 미치는 영향을 조사하였다. APAP 투여 12시간후 DIL 투여군에서 혈청과 간조직의 생화학 분석과 조직학적 관찰에서 간손상의 개선 효과가 확인되었으며, 이는 세포내로의 calcium 유입과 지질과산화의 억제 및 GST의 활성도 증가에 기인한 것으로 보인다. 그러므로 APAP 과량 복용 12시간 후의 DIL 투여는 간손상의 억제에 효과적일 것으로 사료된다.