Stimulation of hepatic mitochondrial alpha-glycerophosphate dehydrogenase and malic enzyme by L-triiodothyronine. Characteristics of the response with specific nuclear thyroid hormone binding sites fully saturated.

Oppenheimer, Jack H.; Silva, Enrique; Schwartz, Harold L.; Surks, Martin I.

doi:10.1172/jci108667

Cited by 153 publications

(65 citation statements)

References 33 publications

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“…This was not a nonspecific effect of IOP because it did not affect the level of the enzyme in hypothyroid pups receiving only tracer [1251]T4 (3 ng). Liver a-GPD also failed to increase with this small dose of T4, which may be accounted for by the minimal elevation of serum T3 and the long latency of this enzyme to respond to thyroid hormone (37). DISCUSSION We have recently described the mechanism of the pituitary response to a failing thyroid gland (reviewed in 13).…”

Section: Resultsmentioning

confidence: 94%

Comparison of Iodothyronine 5′-Deiodinase and Other Thyroid-Hormone-dependent Enzyme Activities in the Cerebral Cortex of Hypothyroid Neonatal Rat

Silva¹,

Larsen²

1982

J. Clin. Invest.

118

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A B S T R A C T Recent studies have shown that -75% of the nuclear 3,5,3'-triiodothyronine (T3) present in adult rat cerebral cortex (Cx) derives from 5'-deiodination of thyroxine (T4) within this tissue. The activity of iodothyronine 5'-deiodinase (I 5'D), the enzyme catalyzing T4 to T3 conversion, increases rapidly after thyroidectomy, suggesting that this could be a compensatory response to hypothyroxinemia. To evaluate this possibility during the period of central nervous system maturation, we studied several thyroid hormone-responsive enzymes (aspartic transaminase [AT], succinic dehydrogenase [S.D.], and Na/K ATPase) in the Cx of 2-, 3-, and 4-wk-old rats. The rats were made congenitally hypothyroid by placing 1, 2, 5, and 20 mg methimazole (MMI) in 100 ml of the mothers' drinking water from day 16 of gestation throughout the nursing period and to the litters after weaning. In addition, serum thyroid hormones, I 5'D, and, in some experiments, in vivo T4 to T3 conversion in Cx were measured in the same pups. Serum T4 concentrations varied from <1 to 40 ng/ml and were generally inversely related to maternal MMI dose. Serum T3 was less affected by MMI than was T4. At 2 wk, decreases in AT, S.D., and ATPase were present in the 20-mg-MMI group but not in the 5-mg-MMI pups despite low serum T4 (<10 ng/ml) in the latter. At 3 and 4 wk, both 5-and 20-mg-MMI groups had significant reductions in these cortical enzymes despite a normal serum T3 in the 5-mg-MMI rats. Cortical I 5'D activity was 10-fold the control value in 5-and 20-mg-MMI animals at 2 wk but increased only three-to fivefold at 3 and 4 wk. I 5'D correlated inversely with serum T4 (r 2 0.96) at all ages, but the less marked elevation of this enzyme in 3-and 4-wk-old pups was not accompanied by an increase in serum T4. Serum T3 increased or remained the same between 2 and 3 wk. These results suggested that the 10-fold increase in I 5'D at 2 wk protected the 5-mg-MMI group from tissue hypothyroidism, but that the three-to fivefold increase at 3 and 4 wk could not. Injection of -250 ng T4/100 g body weight to 2-wk-old, 20-mg-MMI pups (onesixth the normal T4 production rate) led to both a 1.8-ng/g cortical tissue increment in cortical T3 and a significant increase in AT at 24 h, compared with a 0.38-ng/g cortical tissue T3 increment and no change in AT in euthyroid controls. The larger increment in T3 of the 20-mg-MMI pups was due in great part to increased fractional T4 to T3 conversion. Although the latter resulted in greater serum T3 concentrations, three-fourths of the newly formed T3 in the cortex was generated in situ, and it was blocked by iopanoic acid as was the increase in AT. We conclude that 70-80% of the T3 in the Cx of the neonatal rat is produced locally. Serum T4 appears to serve both as a precursor for T3 and as a critical signal for increases in cortical I 5'D. The increased I 5'D can result in normal or nearnormal cerebrocortical T3 concentrations despite marked reductions in serum T4. This mechanism seems to be particularly effective aro...

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Section: Resultsmentioning

confidence: 94%

Comparison of Iodothyronine 5′-Deiodinase and Other Thyroid-Hormone-dependent Enzyme Activities in the Cerebral Cortex of Hypothyroid Neonatal Rat

Silva¹,

Larsen²

1982

J. Clin. Invest.

118

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“…α-Glycerol phosphate dehydrogenase (α-GPD) was assayed as described previously (35,36), at 35°C in 65 mM sodium phosphate buffer (pH 7.4) containing 1 mM KCN, 50 mM α -glycerophosphate, 1.7 mM iodonitrotetrazolium violet, and 50-100 µg of mitochondrial protein.…”

Section: Animals and Drugsmentioning

confidence: 99%

Thyroid hormone–sympathetic interaction and adaptive thermogenesis are thyroid hormone receptor isoform–specific

Ribeiro¹,

Carvalho²,

Schultz³

et al. 2001

J. Clin. Invest.

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In newborns and small mammals, cold-induced adaptive (or nonshivering) thermogenesis is produced primarily in brown adipose tissue (BAT). Heat production is stimulated by the sympathetic nervous system, but it has an absolute requirement for thyroid hormone. We used the thyroid hormone receptor-β-selective (TR-β-selective) ligand, GC-1, to determine by a pharmacological approach whether adaptive thermogenesis was TR isoform-specific. Hypothyroid mice were treated for 10 days with varying doses of T3 or GC-1. The level of uncoupling protein 1 (UCP1), the key thermogenic protein in BAT, was restored by either T3 or GC-1 treatment. However, whereas interscapular BAT in T3-treated mice showed a 3.0°C elevation upon infusion of norepinephrine, indicating normal thermogenesis, the temperature did not increase (<0.5°C) in GC-1-treated mice. When exposed to cold (4°C), GC-1-treated mice also failed to maintain core body temperature and had reduced stimulation of BAT UCP1 mRNA, indicating impaired adrenergic responsiveness. Brown adipocytes isolated from hypothyroid mice replaced with T3, but not from those replaced with GC-1, had normal cAMP production in response to adrenergic stimulation in vitro. We conclude that two distinct thyroid-dependent pathways, stimulation of UCP1 and augmentation of adrenergic responsiveness, are mediated by different TR isoforms in the same tissue.

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“…To determine whether thyroid hormones affected testicular CYP1B1 expression, hypophysectomized adult male rats were treated with T 3 (2 mg/kg/day), T 4 (50 g/kg/day), or an equivalent volume of the vehicle by once-daily subcutaneous injections for 7 consecutive days. The dosages of T 3 and T 4 are supraphysiological and receptor-saturating (Oppenheimer et al, 1977) and have been reported to render hypophysectomized rats euthyroid (Ram and Waxman, 1990). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Developmental Expression and Endocrine Regulation of CYP1B1 in Rat Testis

Leung¹,

Kawai²,

Tai³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Mammalian testis expresses xenobiotic-metabolizing enzymes, including cytochrome P450 1B1 (CYP1B1), which catalyzes the bioactivation of procarcinogens and other chemicals. The factors that control testicular expression of CYP1B1 are largely not known. In the present study, we investigated the influence of age and pituitary, gonadal, and thyroid hormones on CYP1B1 expression in rat testis. Immunoblot analysis showed that testicular CYP1B1 protein was expressed at a level of 5.9 ؎ 2.0 (mean ؎ S.E.M.) pmol/mg microsomal protein in prepubertal 22-day-old rats, whereas it was 6.6-fold greater in pubertal rats (34 days old) and 9.6-fold greater in adult rats (84-91 days old). Hypophysectomy decreased testicular CYP1B1 protein levels by 69% in adult rats when compared with intact rats of the same age. Intermittent subcutaneous administration of growth hormone to hypophysectomized adult rats further decreased it by 63%. Luteinizing hormone (LH) and follicle-stimulating hormone increased CYP1B1 expression in hypophysectomized rats, but they did not restore protein levels to those in intact adult male rats. Prolactin treatment alone had no effect; however, it potentiated the increase in CYP1B1 mRNA and protein expression by LH. 3,5,3-Triiodothyronine, but not thyroxine, resulted in a small increase in testicular CYP1B1 protein levels. Likewise, treatment of hypophysectomized rats with testosterone propionate elicited a small increase in CYP1B1 protein expression. In contrast, treatment of intact adult male rats with 17␤-estradiol benzoate decreased it by 91%. Overall, our findings indicate that rat testicular CYP1B1 protein expression is subject to developmental and endocrine control, with multiple hormones playing a role.

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Stimulation of hepatic mitochondrial alpha-glycerophosphate dehydrogenase and malic enzyme by L-triiodothyronine. Characteristics of the response with specific nuclear thyroid hormone binding sites fully saturated.

Cited by 153 publications

References 33 publications

Comparison of Iodothyronine 5′-Deiodinase and Other Thyroid-Hormone-dependent Enzyme Activities in the Cerebral Cortex of Hypothyroid Neonatal Rat

Comparison of Iodothyronine 5′-Deiodinase and Other Thyroid-Hormone-dependent Enzyme Activities in the Cerebral Cortex of Hypothyroid Neonatal Rat

Thyroid hormone–sympathetic interaction and adaptive thermogenesis are thyroid hormone receptor isoform–specific

Developmental Expression and Endocrine Regulation of CYP1B1 in Rat Testis

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