COMPARISON OF THE EFFECTS OF PROPYLTHIOURACIL, AMIODARONE, DIPHENYLHYDANTOIN, PHENOBARBITAL, AND 3-METHYLCHOLANTHRENE ON HEPATIC AND RENAL-T4 METABOLISM AND THYROID-GLAND FUNCTION IN RATS
COMPARISON OF THE EFFECTS OF PROPYLTHIOURACIL, AMIODARONE, DIPHENYLHYDANTOIN, PHENOBARBITAL, AND 3-METHYLCHOLANTHRENE ON HEPATIC AND RENAL-T4 METABOLISM AND THYROID-GLAND FUNCTION IN RATS
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DOI：
10.1016/0041-008x(91)90030-i
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发表时间：
1991-11-01
影响因子：
3.8
通讯作者：
RICHERT, L
中科院分区：
文献类型：
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作者：
DESANDRO, V;CHEVRIER, M;RICHERT, L
我们研究了丙基硫氧嘧啶（PTU），胺碘酮（AMIO），苯乙内酰脲（DPH），苯巴比妥（PB），3-甲基胆蒽（MC）对甲状腺组织形态学的影响，对参与内源性和外源性代谢的肝和肾酶，以及对治疗7天和14天后甲状腺激素的血浆水平和药代动力学。PTU和PB通过降低血清四碘甲状腺原氨酸（T_4）和三碘甲状腺原氨酸（T_3），引起血清促甲状腺激素（TSH）大量升高，从而引起甲状腺肥大。AMIO和MC通过分别降低血清T3和T4，也引起TSH升高，但程度较小，不足以引起甲状腺肥大。肝5′-脱碘酶活性降低。这种酶的抑制PTU证明在体外：AMIO还降低了酶活性的一个尚未阐明的机制，这可能需要完整的细胞质膜，而在PB-和MC-治疗的大鼠酶活性的降低肯定是由于血清中T4浓度的降低。在PTU处理的大鼠中，可能在MC处理的大鼠中，循环甲状腺激素的减少主要是由于甲状腺合成和/或分泌受损。相反，在PB处理的大鼠中，血清甲状腺激素水平的降低似乎是由于这些激素的排泄增加，因为T4血清清除率显著增加。PB是一种微粒体酶诱导剂，可增加细胞色素b5和P450的含量以及细胞色素P450依赖的戊氧基试卤灵的O-脱戊基化。另一种酶诱导剂MC不影响细胞色素b5和P450的水平，但增加了细胞色素P450依赖的乙氧基试卤灵的O-脱乙基化。PB增加吗啡的葡萄糖醛酸化，而MC增加1-萘酚的葡萄糖醛酸化。然而，血清T4清除率，主要是由其肝结合率，仅在PB治疗的大鼠增加。本研究表明，在解释慢性毒理学和致癌性研究结果时，应考虑肝脏/肾脏与甲状腺之间的密切代谢关系。
We studied the effects of propylthiouracil (PTU), amiodarone (AMIO), diphenylhydantoin (DPH), phenobarbital (PB), and 3-methylcholanthrene (MC) on thyroid histomorphology, on the hepatic and renal enzymes involved in endogenous and exogenous metabolism, and on the plasma levels and pharmacokinetics of thyroid hormones after 7 and 14 days of treatment. PTU and PB, by decreasing both serum tetraiodothyronine (T4) and triiodothyronine (T3), induced a massive increase in serum thyrotropin (TSH) and thus induced thyroid hypertrophy. AMIO and MC, by decreasing respectively serum T3 and T4, also induced an increase of TSH, but to a lesser extent, not sufficient to induce thyroid hypertrophy. Hepatic 5′-deiodinase activity was decreased in all treated rats. Inhibition of this enzyme by PTU was demonstrated in vitro: AMIO also decreased the enzyme activity by a still unelucidated mechanism, which probably requires intact cell plasma membranes, whereas in PB- and MC-treated rats the decrease in enzyme activity certainly resulted from decreased serum concentrations of T4. In PTU-treated rats, and probably in MC-treated rats, decreases in circulating thyroid hormones were primarily due to impairment of synthesis and/or of secretion by the thyroid. In contrast, in PB-treated rats, the decrease in serum thyroid hormone levels seems to be due to increased excretion of these hormones, as T4 serum clearance was significantly increased. PB, a microsomal enzyme inducer, increased the cytochrome b5and P450 content as well as the cytochrome P450-dependent O-depentylation of pentoxyresorufin. The other type of enzyme inducer, MC, did not affect cytochrome b5and P450 levels, but did increase the cytochrome P450 dependent O-deethylation of ethoxyresorufin. PB increased the glucuronidation of morphine, whereas MC increased the glucuronidation of 1-naphthol. However, serum T4 clearance, mainly determined by its hepatic conjugation rate, was increased only in PB-treated rats. It appears from this study that the close metabolic relationship between the liver/kidney and the thyroid should be taken into consideration when the findings of chronic toxicology and carcinogenicity studies are interpreted.