Bailie M B, Jean P A, Lappin P B, Scozzaro M J, Schmidt T M, Moulin F J, Roth R A
Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824, USA.
Toxicol Appl Pharmacol. 1995 Sep;134(1):63-70. doi: 10.1006/taap.1995.1169.
alpha-Naphthylisothiocyanate (ANIT) is a cholangiolitic hepatotoxicant that causes periportal hepatic injury in the rat that is neutrophil- and platelet-dependent. Since macrophages have recently been implicated as participants in some chemically induced hepatotoxicities, we evaluated the role of these cells in ANIT-induced hepatic injury. Rats were treated with gadolinium chloride (GdCl3), an agent which decreases hepatic macrophage numbers and activity, zymosan, an agent which increases hepatic macrophage numbers, or vitamin A, which increases hepatic macrophage activity. GdCl3 did not ameliorate ANIT-induced hepatotoxicity, as demonstrated by a lack of attenuation of any of the markers of hepatic insult evaluated. In contrast, pretreatment with either zymosan or vitamin A decreased ANIT hepatotoxicity. Zymosan administration reduced blood neutrophil numbers and influx of neutrophils into the peritoneum after intraperitoneal glycogen administration but did not affect hepatic neutrophil accumulation in ANIT-treated rats. To determine if macrophages were important in the protection by vitamin A, rats were cotreated with GdCl3 and vitamin A. GdCl3 did not alter the protection from ANIT hepatotoxicity afforded by vitamin A. Vitamin A treatment decreased ANIT and glutathione concentrations in bile at 1 and 4 hr after ANIT administration but had a minimal effect on plasma ANIT concentration. In summary, pretreatment of rats with zymosan or vitamin A but not GdCl3 attenuated ANIT-induced liver injury. The protection afforded by zymosan may derive from its effects on neutrophils or platelets. The protection by vitamin A appears to result from its effect on the transport of ANIT into bile. The results suggest that hepatic macrophages are not required for the manifestation of ANIT hepatotoxicity.
α-萘基异硫氰酸酯（ANIT）是一种引起胆管炎的肝毒性物质，可导致大鼠门静脉周围肝损伤，这种损伤依赖于中性粒细胞和血小板。由于最近有研究表明巨噬细胞参与了某些化学诱导的肝毒性作用，我们评估了这些细胞在ANIT诱导的肝损伤中的作用。给大鼠分别注射氯化钆（GdCl3），一种可减少肝脏巨噬细胞数量和活性的药物；酵母聚糖，一种可增加肝脏巨噬细胞数量的药物；或维生素A，一种可增加肝脏巨噬细胞活性的药物。结果表明，GdCl3并未改善ANIT诱导的肝毒性，所评估的任何肝损伤标志物均未出现衰减。相反，用酵母聚糖或维生素A预处理可降低ANIT的肝毒性。给予酵母聚糖可减少腹腔注射糖原后血液中的中性粒细胞数量以及中性粒细胞向腹膜的流入，但不影响ANIT处理大鼠肝脏中的中性粒细胞聚集。为了确定巨噬细胞在维生素A的保护作用中是否重要，将大鼠同时用GdCl3和维生素A进行处理。GdCl3并未改变维生素A对ANIT肝毒性的保护作用。维生素A处理可降低ANIT给药后1小时和4小时胆汁中ANIT和谷胱甘肽的浓度，但对血浆ANIT浓度影响极小。总之，用酵母聚糖或维生素A而非GdCl3预处理大鼠可减轻ANIT诱导的肝损伤。酵母聚糖提供的保护作用可能源于其对中性粒细胞或血小板的影响。维生素A的保护作用似乎是由于其对ANIT向胆汁转运的影响。结果表明，ANIT肝毒性的表现并不需要肝脏巨噬细胞的参与。
