Agrawal A K, Shapiro B H
Laboratories of Biochemistry, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA 19104-6048, USA.
Drug Metab Dispos. 1997 Nov;25(11):1249-56.
Newborn male and female rat pups were injected with either 2 mg or 4 mg monosodium aspartate (MSA)/g body weight or diluent on alternate days for the first 9 days of life. Both doses of the amino acid had profound effects on the sexually dimorphic growth hormone secretory profiles in adulthood. There were no measurable levels of growth hormone in any of the plasma samples obtained during 8 continuous hr of serial blood collections from the adult males and females treated neonatally with 4 mg of MSA. Male rats treated with half the dose of the amino acid (i.e., 2 mg MSA/g) exhibited typical masculine profiles of growth hormone release, except that the amplitudes of the ultradian pulses were reduced to 10-20% of normal male levels. Otherwise, like normal males, the peaks occurred about every 3-4 hr and the intervening 2.5-hr troughs had undetectable levels of growth hormone. In a similar sense, females treated with 2 mg of MSA maintained their sexually dimorphic pattern of plasma growth hormone, i.e., frequent pulses of hormone followed by short-lived troughs. However, the peaks rarely exceeded 20 ng/ml and the troughs usually fell to a measurable 8 to 10 ng/ml resulting in an approximate 75% reduction in the mean plasma concentration. Growth hormone- and gender-dependent expression of CYP2C7, 2C11, 2C12, 2C13, 2A1, 2A2, and 3A2 (mRNAs, proteins, and catalytic activities) were generally unaffected by neonatal exposure to 2 mg of MSA. In contrast, the higher 4-mg dose of the amino acid completely or near completely suppressed male-specific CYP2C11, 2C13, 2A2, and 3A2 expression while inducing small increases in female-specific CYP2C12 and female-predominant CYP2A1 in the treated males. Females exposed to the 4 mg MSA dose exhibited less severe isoform changes characterized by small reductions in CYP2C12 and 2C7 levels. Whereas expression levels of most of the CYP isoforms in both sexes were lowest in the pubertal (47-day-old) rats, and occasionally higher in the adults (207-day-old) as compared with the early postpubertal (70-day-old) rats, the effects of neonatal MSA were the same at all ages studied. Since each of the CYP isoforms are regulated by different "signaling elements" in the sexually dimorphic plasma growth hormone profiles, it is possible to correlate MSA-induced alterations in CYP expression levels to specific changes in the gender-dependent growth hormone profiles.
新生雄性和雌性大鼠幼崽在出生后的前9天，每隔一天注射2毫克或4毫克天冬氨酸钠（MSA）/克体重或稀释剂。这两种剂量的氨基酸对成年期性二态性生长激素分泌模式都有深远影响。在对新生时用4毫克MSA处理的成年雄性和雌性大鼠进行连续8小时的系列采血过程中，所采集的任何血浆样本中都没有可测量的生长激素水平。用半剂量氨基酸（即2毫克MSA/克）处理的雄性大鼠表现出典型的雄性生长激素释放模式，只是超日脉冲的幅度降至正常雄性水平的10 - 20%。否则，与正常雄性一样，峰值大约每3 - 4小时出现一次，中间2.5小时的谷值期生长激素水平检测不到。同样，用2毫克MSA处理的雌性大鼠维持了其血浆生长激素的性二态模式，即激素频繁脉冲后接着短暂的谷值期。然而，峰值很少超过20纳克/毫升，谷值通常降至可测量的8至10纳克/毫升，导致平均血浆浓度降低约75%。新生儿接触2毫克MSA一般不会影响生长激素和性别依赖性的CYP2C7、2C11、2C12、2C13、2A1、2A2和3A2（mRNA、蛋白质和催化活性）的表达。相比之下，较高的4毫克剂量的氨基酸完全或几乎完全抑制了雄性特异性的CYP2C11、2C13、2A2和3A2的表达，同时在处理过的雄性大鼠中诱导雌性特异性的CYP2C12和雌性占主导的CYP2A1有小幅增加。接触4毫克MSA剂量的雌性大鼠表现出的同工型变化不那么严重，其特征是CYP2C12和2C7水平有小幅降低。虽然两性中大多数CYP同工型的表达水平在青春期（47日龄）大鼠中最低，与青春期后早期（70日龄）大鼠相比，在成年期（207日龄）偶尔会更高，但在所有研究的年龄阶段，新生儿MSA的影响都是相同的。由于每种CYP同工型在性二态性血浆生长激素模式中受不同的“信号元件”调节，因此有可能将MSA诱导的CYP表达水平变化与性别依赖性生长激素模式的特定变化联系起来。
