How strong Is the evidence that upon metabolic saturation that the parent compound is producing the cytotoxicity?

Answer Explanations

• Moderate evidence

  Expert 4
  It is generally assumed that the parent compound is producing observed cytotoxicity, based on investigations into reactive intermediates of 1,4-DX which have failed to generate evidence of DNA reactivity and repair, protein binding, or enhancement of cytotoxicity after induction of xenobiotic biotransformation. Pretreatment with inducers of mixed-function oxidases also did not significantly change the extent of covalent binding in subcellular fractions (Lacanfroni et al., 2023). Based on comparison of the extent and nature of the data available with that for other compounds with which I'm familiar, I consider the strength of the evidence to be moderate.
• Strong evidence

  Expert 2
  The data from studies of damage in mitochondria provide firm evidence for oxidative stress as an early event. In addition, the findings of DNA double strand breaks, including their greater onset in the setting of decreased antioxidant defenses, provide strong evidence for the consequential serious genome damage, which should be sufficient for impairing cell survival/growth and leading to pressures for the emergence of alternative cell populations.     
• Weak evidence

  Expert 3
  The cyp2e1 KO data indicate parent DX per se may not be the key driver of cytotoxicity, i.e., in the absence of 2e1, much of DX toxicity is attenuated (even though the KO mice should be exhibiting substantially higher parent DX).  These data indicate it the actual cyp2e1 induction and its associated biology (e.g. oxidative stress) that is the primary event responsible for ensuing toxicity.  Further TK assessments in KO vs WT mice could inform this consideration.   However, given that 2e1 KO does not completely attenuate toxicity, it may be evidence of some direct-acting DX toxicity potential (e.g., it might be informative to see if CAR and/or AhR receptor activation might be present in KO mice - i.e., these receptors may have a very high Km for DX activation that can only be functionally active act relatively high tissue concentrations associated with a substantive loss of the primary  metabolic detoxification route of DX),
• Strong evidence

  Expert 6
  The animal data seen together with the toxicokinetic information strongly point to this conclusion. The fact that the DX metabolit(s) are not realistically to be considered as the reactive agent(s) supports this conclusion  
• Moderate evidence

  Expert 5
  The data suggests that cytotoxicity may play a role in the 1,4 DX.  Further analysis and possible experimental approaches may be needed to completly resolve the issues specifically linking the dose wth the tumor induction and induction of cell proliferation.  The initial events to start the carcinogenic cascade whether be oxidative damage or direct cytotoxicity via metabolic saturation may be resolved from a complete dose response evaluation with correlation to the the MOA key events.  This is for liver. The other two tumor sites require  the development of a hypothesized  MOA (with key events).    
• Weak evidence

  Expert 1
  The ring opening metabolism of 1,4DX by Cyp2e1 to generate metabolites that can redox cycle and the "leakage" of ROS from Cyp2e1 at saturating levels (i.e., always "on" and highly induced) are likely the sources of cytotoxic effects not the parent compound itself.