Read the summary and the most important questions on mechanistic toxicology | 0-8493-7272-0 | Uls A. Boelsterli

• 1 Introduction

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• For what reason is molecular toxicology/ mechanisms of toxicology required?

  required to:
  - estimate the risk of human toxicity after exposure to a potentially toxic compound
  - Determine toxicity threshold
  - Develop antidotes against acute toxicity
  - Facilitate development of safe pharmaceuticals
  - develop biomarkers for exposure or toxicity

• What are believed to be some mechanims behind the muscle atrophy induced by statins?

  toxicokinetics: impaired catalytic activity of CYPs, inhibition of p-gp etc.

• What are the mechanims that lay behind the thalidomide embryotoxicity?

  - during day 24 and 33 of pregnancy
  - maybe: accumulation of toxic metabolites,
  - Also some abnormalities in eyes and ears.
  - Thalidomide can intercalate into the DNA and it can inhibit the angiogenesis.
  - Thalidomide can inhibit the expression of specific cell-adhesion molecules: integrines which play a pivotal role in cell growth and differentiation.
  - Thalidomide can inhibit a number of specific growth factors.
  - Integrins can stimulate angiogenesis
  - The promoters in the DNA for integrins are guanine rich.
  - Thalidomide exists in a racemic form. Only the S-enantiomer is teratogenic, so it is sterospecific.

• 2 Types of toxic responses

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• What are the intrinsic properties of toxicity of xenobiotics? And what is the exposure?

  What is the effect of a compound on a cell. At which concentration at the target does the effect occur (potency)
  exposure: Which concentration is reached at the target.

• Which three things can toxicokinetic factors and toxicodynamic factors explain?

  - species differences
  - gender differences
  - organ-selective toxicity

• What is the difference between adaptation and a stress response?

  Adaptation: To more effectively deal with the drug load. like an upregulation of genes encoding for drug metabolizing enzymes or transporters to eliminate xenobiotics.  example: upregulation of cyp which will result in an increase in liver weight. 
  
  A stress response can be e.g.:
  - An activation of defense mechanisms via Nrf2,  c-jun via stress-activated protein kinases. (stress sensors)
  - upregulation of antioxidants, heat shock proteins
  - endoplasmatic reticulum stress response: refolding of denatured proteins (Hsp)
  To limit the damage done, final outcome is balance between toxic event and protecting events.

• What are examples of toxic responses?

  - cell dead: apoptosis, necrosis
  - pharmacological/physiological effects
  - genotoxicity/ mutagenicity
  - carcinogenicity
  - reproduction toxicity, incl. teratogenicity
  - neurotoxicity
  - immunotoxicity, sensation
  - irritation (skin, eye)

• To which toxic responses can covalent binding lead?

  - Degenerative disorders
  - cell death
  - immune toxicity
  - mutagenesis
  - carcinogenesis
  - embryotoxicity
  - idiosyncratic toxicity

• To which toxicological responses can oxidative stress lead?

  - Degenerative disorders
  - cell death
  - inflammation
  - mutagenesis
  - carcinogenesis
  - embryotoxicity
  - idiosyncratic reactions

• What are mechanisms of cytoprotecive effects of prostaglandines?

  - They are involved in the upregulation of heat shock proteins in the liver in a stress liver. Hsps are necessary for proper protein folding and trafficking, they are involved in signal transduction and they can even protect from apoptosis. So, if prostaglandin synthesis is inhibited then the liver has a reduced capacity to upregulate the hsps. (like cox-inhibitors. )