L-thyroxine

L-Thyroxine (Levothyroxine; T4) is a synthetic hormone in the treatment of hypothyroidism. DIO enzymes convert biologically active thyroid hormone (Triiodothyronine,T3) from L-Thyroxine (T4).

Signaling Pathways >> Others >> Thyroid Hormone Receptor

Research Areas >> Endocrinology

Natural Products >> Others

Human Endogenous Metabolite

Deiodinases (DIOs), which catalyse the conversion of thyroxine (pro-hormone) to the active thyroid hormone, are associated with thyroid stimulating hormone (TSH) levels. DIO1 and DIO2 catalyze activation of thyroid hormone secretion in contrast to DIO3 playing role inactivation of the secretion. Activities of DIO1 and DIO2 play pivotal role in the negative feedback regulation of pituitary TSH secretion[1]. L-Thyroxine (T4) and Triiodothyronine (T3) hormones are known to modulate the expression of ionic channels, pumps and regulatory contractile proteins. Moreover, thyroid hormones have been shown to influence calcium homeostasis and flux responsible for excitation and contractility, with L-Thyroxine and Triiodothyronine modulating its pharmacological control and secretion. In rats fed 12 weeks with the iodine-free diet, a significant decrease in the levels of both Triiodothyronine and L-Thyroxine is observed when compared to the control group fed with standard diet (p<0.001). In the group treated with low doses of L-Thyroxine, an increase in L-Thyroxine levels is observed (p=0.02) while Triiodothyronine levels remain virtually similar to the control group (p=0.19). Rats treated with high doses of L-Thyroxine display a significant increase in both Triiodothyronine and L-Thyroxine circulating concentrations compared to the non-treated hypothyroid group (p<0.001 and p=0.004, respectively) and a significant increase in L-Thyroxine levels when compared to the control values (p=0.03)[2].

Rats[2] Sprague-Dawley female rats (N=22) are used. Non-pregnant rats are divided into four groups: 1) control, 2) hypothyroidism, 3) hypothyroidism treated with low doses of L-Thyroxine (20 μg/kg/day) and 4) with high doses of L-Thyroxine (100 μg/kg/day). Control rats (group 1) are fed with standard diet, while the intervention rats are fed with iodine-free diet for 12 weeks to induce hypothyroidism (groups 2-4) which is continued for four more weeks to allow screening of hypothyroid status and L-Thyroxine-treatment. Food and water (iodine-free diet) are available ad libitum. The hypothyroid group treated with low (group 3) or high doses of L-Thyroxine (group 4) are injected intraperitoneally every 24 h with respectively 20 μg/kg/day and 100 μg/kg/day. Blood samples are collected for thyroid function screening at week 12 and 16 following the initiation of either the control or iodine-free diet. Hysterectomy is performed under general anesthesia (isoflurane 2%) at the end of the treatment and the two uterine horns are placed in physiological Krebs' solution until isometric tension measurements within no more than 1 h.

[1]. Arici M, et al. Association between genetic polymorphism and levothyroxine bioavailability in hypothyroid patients. Endocr J. 2018 Jan 11.

[2]. Corriveau S, et al. Levothyroxine treatment generates an abnormal uterine contractility patterns in an in vitro animalmodel. J Clin Transl Endocrinol. 2015 Sep 9;2(4):144-149.

3-Methyladenine | Hydrocortisone | Acetylcysteine(N-acetylcysteine) | Retinoic acid | Melatonine | Dinoprostone | Nicotinamide | Adenosine triphosphate | 4-Acetamidophenol | Prostaglandin E1 | liothyronine | Dehydroepiandrosterone | Corticosterone | Progesterone | Docosahexaenoic Acid

DATA ITEMS CITED :

15

MOLECULAR FORMULA :

C15-H11-I4-N-O4

MOLECULAR WEIGHT :

776.87

WISWESSER LINE NOTATION :

QVYZ1R CI EI DOR DQ CI EI

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Human - man

DOSE/DURATION :

63 ug/kg

TOXIC EFFECTS :

Behavioral - hallucinations, distorted perceptions Cardiac - pulse rate increase, without fall in BP

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Human - woman

DOSE/DURATION :

400 ug/kg/2D-I

TOXIC EFFECTS :

Behavioral - coma Cardiac - arrhythmias (including changes in conduction)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

2 mg/kg/10D-I

TOXIC EFFECTS :

Liver - other changes Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - monoamine oxidase Biochemical - Metabolism (Intermediary) - effect on mitochondrial function

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

26250 ug/kg

SEX/DURATION :

female 1-21 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - eye/ear

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

1400 ug/kg

SEX/DURATION :

female 16-22 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Newborn - biochemical and metabolic

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

410 mg/kg

SEX/DURATION :

female 3 week(s) pre-mating female 1-20 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - cytological changes (including somatic cell genetic material)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

450 ug/kg

SEX/DURATION :

female 7-15 day(s) after conception

TOXIC EFFECTS :

Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

8160 ug/kg

SEX/DURATION :

female 7 day(s) pre-mating - 5 day(s) post-birth

TOXIC EFFECTS :

Reproductive - Maternal Effects - postpartum

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

600 ug/kg

SEX/DURATION :

female 19-21 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - urogenital system

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Unreported

DOSE :

12 mg/kg

SEX/DURATION :

male 6 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Fertility - mating performance (e.g. # sperm positive females per # females mated; # copulations per # estrus cycles)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

12 mg/kg

SEX/DURATION :

female 9-11 day(s) after conception

TOXIC EFFECTS :

Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants) Reproductive - Specific Developmental Abnormalities - musculoskeletal system

MUTATION DATA

TEST SYSTEM :

Rodent - rat

DOSE/DURATION :

6250 ug/kg/2D (Continuous)

REFERENCE :

BEXBAN Bulletin of Experimental Biology and Medicine (English Translation). Translation of BEBMAE. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.41- 1956- Volume(issue)/page/year: 72,942,1971 *** NIOSH STANDARDS DEVELOPMENT AND SURVEILLANCE DATA *** NIOSH OCCUPATIONAL EXPOSURE SURVEY DATA : NOHS - National Occupational Hazard Survey (1974) NOHS Hazard Code - M0234 No. of Facilities: 68 (estimated) No. of Industries: 1 No. of Occupations: 6 No. of Employees: 2770 (estimated) NOES - National Occupational Exposure Survey (1983) NOES Hazard Code - M0234 No. of Facilities: 717 (estimated) No. of Industries: 4 No. of Occupations: 9 No. of Employees: 10666 (estimated) No. of Female Employees: 7298 (estimated)