Pampori N A, Agrawal A K, Waxman D J, Shapiro B H
Laboratories of Biochemistry, University of Pennsylvania School of Veterinary Medicine, Philadelphia 19104-6048.
Biochem Pharmacol. 1991 May 1;41(9):1299-309. doi: 10.1016/0006-2952(91)90101-a.
Neonatal male rats were treated with monosodium glutamate (MSG) at either 0.5, 1.0, 2.0, 3.0 or 4.0 mg/g body weight on alternate days during the first 9 days of life. As adults, rats were catheterized to obtain unstressed, serial blood samples for the determination of ultradian patterns of circulating growth hormone. In addition, the levels of drug-metabolizing enzymes (i.e. hexobarbital hydroxylase, cytochromes P450 and b5, NADPH-cytochrome P450 reductase and ethoxyresorufin O-deethylase) as well as sex-dependent forms of cytochrome P450 [i.e. male-dependent cytochromes P450 2c (IIC11), 2a (IIIA2) and RLM2 (IIA2) and female-dependent cytochromes P450 2d (IIC12) and 3 (IIA1)] and/or their catalytic activities were measured in the hepatic microsomes of the treated rats. The results demonstrated a dose-dependent, graded response to MSG treatment. As the dose of MSG increased from 0.5 to 4.0 mg, there was a concurrent decline in the amplitudes of the characteristically masculine, episodic bursts of growth hormone, until at the highest dose (4 mg), the pulses were no longer detectable. Associated with this dose-dependent alteration in the ultradian pattern of growth hormone secretion was a measurable change in the activities of the sex-dependent hepatic enzymes. As the pulse heights of the hormone declined to 10-20% of their normal amplitudes, the levels of the male-dependent enzymes (i.e. the drug-metabolizing enzymes, as well as the male forms of cytochrome P450 and their specific steroid hydroxylases) were maintained, and in some cases, exceeded the levels normally found in males. However, as the hormone pulse heights declined, there appeared an accompanying increase in the activities of some of the female-dependent enzymes. Finally, with the loss of all detectable levels of circulating growth hormone, the normal masculine profile of hepatic enzymes was reversed to an apparently normal (with the exception of cytochrome P450 2d) feminine profile. Summarizing, the results indicate that (1) neonatal administration of MSG can produce dose-dependent, graded, long-term developmental defects in the ultradian rhythm of circulating growth hormone and associated sex-dependent hepatic enzymes, and (2) while the male-dependent hepatic enzymes can be maintained at normal or even higher levels in the face of an up to 90% reduction in the pulse heights of plasma growth hormone, the activities of the female-dependent enzymes may begin to increase.
新生雄性大鼠在出生后的前9天，每隔一天接受0.5、1.0、2.0、3.0或4.0毫克/克体重的谷氨酸单钠（MSG）处理。成年后，将大鼠插管以获取无应激的系列血样，用于测定循环生长激素的超日节律。此外，还测定了药物代谢酶（即己巴比妥羟化酶、细胞色素P450和b5、NADPH-细胞色素P450还原酶和乙氧基试卤灵O-脱乙基酶）的水平，以及细胞色素P450的性别依赖性形式[即雄性依赖性细胞色素P450 2c（IIC11）、2a（IIIA2）和RLM2（IIA2），以及雌性依赖性细胞色素P450 2d（IIC12）和3（IIA1）]和/或它们在处理过的大鼠肝微粒体中的催化活性。结果表明，对MSG处理存在剂量依赖性的分级反应。随着MSG剂量从0.5毫克增加到4.0毫克，雄性特有的、间歇性生长激素脉冲的幅度同时下降，直到最高剂量（4毫克）时，脉冲不再可检测到。与生长激素分泌超日节律的这种剂量依赖性改变相关的是，性别依赖性肝酶的活性发生了可测量的变化。随着激素脉冲高度下降到正常幅度的10%-20%，雄性依赖性酶（即药物代谢酶，以及细胞色素P450的雄性形式及其特定的类固醇羟化酶）的水平得以维持，在某些情况下，超过了雄性正常水平。然而，随着激素脉冲高度下降，一些雌性依赖性酶的活性出现了伴随性增加。最后，随着循环生长激素所有可检测水平的丧失，肝酶的正常雄性特征逆转至明显正常（细胞色素P450 2d除外）的雌性特征。总之，结果表明：（1）新生期给予MSG可在循环生长激素的超日节律以及相关的性别依赖性肝酶中产生剂量依赖性、分级的长期发育缺陷；（2）尽管面对血浆生长激素脉冲高度高达90%的降低，雄性依赖性肝酶仍可维持在正常甚至更高水平，但雌性依赖性酶的活性可能开始增加。
