Shimamoto Y, Kitamura H, Iwai M, Saito M, Kazusaka A, Fujita S
Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Arch Toxicol. 1999 Feb;73(1):41-9. doi: 10.1007/s002040050584.
We previously reported that lipoplysaccharide (LPS) injected intracerebroventricularly (i.c.v.) at an ineffective dose (0.1 microgram/rat) decreased the drug metabolizing activities and related cytochrome P450 (CYP) isozymes in rat liver microsomes when injected intraperitoneally (i.p.). The dose study (doses < 0.1 microgram intracerebrally and > 0.1 microgram i.p.), which was carried out to examine how much more effective is i.c.v.-LPS than i.p.-LPS, showed that the pattern of alteration of expression of CYP isozymes induced by i.c.v.-LPS was different from that caused by i.p.-LPS at an effective dose (10 micrograms/rat). These results indicate that the decrease in hepatic CYP isozymes caused by i.c.v.-LPS could not be explained by the LPS leaked from the brain, suggesting that the decrease in hepatic CYP isozymes by i.c.v.-LPS may be caused by a central action of LPS. In this study, the possible involvement of sympathetic nervous and adrenocortical systems in the down-regulation of CYP isozymes by i.c.v.-LPS was investigated using surgical or chemical sympathetecomized or adrenalectomized rats. The norepinephrine (NE) content in the liver in rats with surgical hepatic sympathetectomy was reduced by 88% compared with that of sham-operated rats that received i.c.v.-saline and 85% compared with that of sham-operated rats that received i.c.v.-LPS, indicating that hepatic denervation was successful. The NE content in the liver in rats chemically sympathetectomized by two i.p. injections of 6-hydroxydopamine (40 mg/kg each time) 1 and 2 days before i.c.v. injection was reduced by 82% in i.c.v.-saline-treated and by 74% in i.c.v.-LPS-treated groups compared with that in rats pretreated with i.p.-saline. These results indicate that sympathetic NE terminals were effectively removed. Intracerebroventricular LPS decreased the total P450 content and the activities of CYP dependent drug metabolizing enzymes, ethoxyresorufin O-deethylase (EROD), pentoxyresorufin O-depentylase (PROD), imipramine N-demethylase (IMND) and erythromycin N-demethylase (ERND) after 24 h in both sympathetectomized rats and non-denervated rats. Adrenalectomy (ADX) reduced the level of corticosterone in serum by 81% compared to sham-operated rats, indicating that adrenalectomy was successful. ADX did not inhibit the decrease in the total P450 content and the metabolism of drugs induced by i.c.v.-LPS, but more profoundly emphasized the inhibitory effect of i.c.v.-LPS than the sham-operation. These results suggest that the sympathetic nervous systems both directly and indirectly innervating the liver do not participate in the primary mechanism of the decrease in the activities of CYP isozymes in rat liver microsomes induced by i.c.v.-LPS. Also, the adrenal glands, especially the adrenocortical system, play a suppressive role in the decrease in CYP isozymes caused by i.c.v.-LPS.
我们之前报道，当以无效剂量（0.1微克/大鼠）脑室内（i.c.v.）注射脂多糖（LPS）后腹腔内（i.p.）注射时，大鼠肝微粒体中的药物代谢活性及相关细胞色素P450（CYP）同工酶会降低。为研究i.c.v.-LPS比i.p.-LPS有效多少而进行的剂量研究（脑内剂量<0.1微克，腹腔内剂量>0.1微克）表明，有效剂量（10微克/大鼠）的i.c.v.-LPS诱导的CYP同工酶表达改变模式与i.p.-LPS引起的不同。这些结果表明，i.c.v.-LPS导致的肝CYP同工酶减少不能用从脑内漏出的LPS来解释，提示i.c.v.-LPS导致的肝CYP同工酶减少可能是由LPS的中枢作用引起的。在本研究中，使用手术或化学去交感神经或肾上腺切除的大鼠，研究了交感神经系统和肾上腺皮质系统在i.c.v.-LPS下调CYP同工酶过程中可能的参与情况。与接受i.c.v.-生理盐水的假手术大鼠相比，手术性肝去交感神经大鼠肝脏中的去甲肾上腺素（NE）含量降低了88%，与接受i.c.v.-LPS的假手术大鼠相比降低了85%，表明肝去神经支配成功。在i.c.v.注射前1天和2天经两次腹腔注射6-羟基多巴胺（每次40毫克/千克）进行化学去交感神经的大鼠，与经腹腔注射生理盐水预处理的大鼠相比，在i.c.v.-生理盐水处理组中肝脏NE含量降低了82%，在i.c.v.-LPS处理组中降低了74%。这些结果表明交感NE终末被有效去除。在去交感神经大鼠和未去神经大鼠中，脑室内注射LPS 24小时后均降低了总P450含量以及CYP依赖性药物代谢酶乙氧异吩唑酮O-脱乙基酶（EROD）、戊氧异吩唑酮O-脱戊基酶（PROD）、丙咪嗪N-脱甲基酶（IMND）和红霉素N-脱甲基酶（ERND）的活性。与假手术大鼠相比，肾上腺切除术（ADX）使血清皮质酮水平降低了81%，表明肾上腺切除术成功。ADX并未抑制i.c.v.-LPS诱导的总P450含量降低和药物代谢，但比假手术更显著地增强了i.c.v.-LPS的抑制作用。这些结果提示，直接和间接支配肝脏的交感神经系统不参与i.c.v.-LPS诱导的大鼠肝微粒体中CYP同工酶活性降低的主要机制。此外，肾上腺，尤其是肾上腺皮质系统，在i.c.v.-LPS导致的CYP同工酶减少中起抑制作用。
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