Teratogenic mechanisms of medical drugs

17 important questions on Teratogenic mechanisms of medical drugs

What is the normal cascade of folate?

The natural form is folate but folic acid has a higher bioavailability.
1) folate can be converted by 2 reduction reactions with dihydrofolate reductase (DHFR) to the naturally bioactive form; tetrahydrofolate (THF).
2) THF can be converted into 5-methyltetrahydrofolate (5-MTHF). This is the main form that is circulating in the blood and can be transported into the tissues.

Via which three ways can 5-MTHF be transported into the tissues?

1) by membrane-associated receptors
2) by a carrier mediated system the reduced folate carrier
3) passive diffusion.

What is the function of 5-MTHF inside the cell?

It acts as an essential co-enzyme by being an acceptor or donor in e.g. purine and pyrimidine synthesis and DNA methylation reactions.
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Why is folate so important during pregnancy?

Rapid proliferating tissues require the most DNA synthesis therefore during the fetal development folate is the most necessary.

What is the first group of folate antagonists?

These inhibit DHFR irreversible by binding to it. This group includes methotrexate, sulfasalazine, triamterene and trimethoprim.  So these drugs make sure that less THF and therefore less 5-MTHF is formed.

What is the second group of folate antagonists?

This group consists of anti-epileptics like valproic acid, phenytoin and carbamazepine. They antagonize other enzymes in the folate metabolism, impair folate absorption or increase folate degradation. These drugs can induce neural tube defects, orofacial clefts and limb defects.

What kind of polymorphisms are associated with the folate metabolism?

1) methylenetetrahydrofolate reductase (MTHFR)
2) methionine synthase reductase (MTRR)
3) methylenetetrahydrofolate dehydrogenase (MTHDFI)

Polymorphisms in these things may lead to differences in the susceptibility of individuals to folate antagonists.

What is the result of folate deficiencies during pregnancy?

- intrauterine death, growth retardation, congenital malformations, neural tube defects. Folic acid supplementation during the gestational period does prevent this.

What kind of role does vitamin B12 play?

This is a cofactor for methionine synthase which converts homocysteine into methionine. It is known that women that carry an infant with a neural tube defect have significantly higher homocysteine levels and decreased methionine levels in plasma and amniotic fluid. Therefore a shortage of vit B12 may also lead to a distorted folate metabolism.

In what way is Bosentan teratogenic?

Its intereferes with the molecular pathways (endothelins, cadherins and integrins) and therefore it may induce neural crest related malformations.

What is the most important signalling molecule in neural crest cell development?

retinoic acid the active form of vitamin A. Both excesses and shortages result in malformations.

How is retinoic acid involved in neural crest cell development?

Embryonic retinoic acid synthesis and degradation is performed by retinal dehydrogenases and CYP26. 
The teratogenicity of retinoids can be due to retinoic acid receptors (RARs) and retinoid X receptors (RXRs). These receptors are transcription factors themselves and affect other genes that are necessary in the development.

Drugs like retinoids that are used for dermatological conditions may alter the retinoid homeostasis.

What are alternative ways by which Endocrine disrupting chemicals can cause male reproductive disorders?

- resistance to anti-Mullerian hormone
- inhibition of enzyms involved in the inactivation of sex steroids.
- disruption of the androgen signalling pathway

Which drugs are known to induces oxidative stress?

thalidomide, phenytoin, valproic acid, class III antiarrhytmica, iron supplements and chemotherapeutic drugs.

What are vascular disruption defects?

This are structural birth defects resulting from interference with a breakdown of the originally formed arteries, veins and capillaries.
vascular disruption refers to disturbances in the blood circulation in the uterine-placental unit, the placental-fetal unit or the fetus itself.

What are examples of drugs that can cause vascular disruption?

aspirin misoprostol, ergotamine and pseudoephedrine

In what way can statins be teratogenic?

Cholesterol is essential in the development of the embryo and may also activate hedgehog morphogens. Statins can inhibit hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase. Cholesterol is the end product of this mevalonate pathway. Therefore statins may induce several birth defects.

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