evolution & the Ah receptor

[ttweed@wildrockies.org (Tony Tweedale)]

  daniel nebert, daniel petersen & albert fornace: 'Cellular response to
  oxidative stress: the (Ah) gene battery as a paradigm' _env health persp's
  (supplements)_ 88:13-25 ('90)
  ---
  
  is an interesting read.  the battery of the 6 known (in '90)  Ah inducible
  genes "encod[e] metabolically coordinated enzymes that respond to
  phytoalexin-induced oxidative cytotox.; in addition, the Ah receptor
  appears to play a role in programmed cell death, or apoptosis."
  
  "apoptosis the programmed death of some cells, so that others may survive.
  such a process normally involves endogenous signals and is seen in
  embryonic development, normal tissue turnover, and hormone-dependant
  atrophy.  we sugguest that a process similar or identical to apoptosis,
  involving exogenous signals (e.g. phytoalexins) might occur during tumor
  promotion (fig. 6).  In the face of chemical adversitye, the primary drive
  for the eukaryotic or prokaryotic [plant] cell is to survive.  in
  eukaryotic cells [bacterial & animal cells, with complex cell membrane in
  place of cell wall, inter alia] it is clear that the Ah gene battery
  participates in this function."
  
  phytoalexins, e.g. the quinones, are  low molec. wt. natural antimicrobials
  in plants, up to 5-10% of plant weight.  they kill microbes because they're
  highly electrophilic--produce free radicals, thereby are mutagens & mutagen
  type carcinogens, interfere w/ the eukaryotic energy cycle (atp/adp,
  nadp/nadph), raise intercellular Ca2+ levels, and generally destroy by
  means of their extreme electron inbalance ie reactivity.  damage control is
  via p450 & flavin containing monooxygenase enzymes.
  
  such cellular damage effects are observed in apoptosis.  TCDD/Ah and
  glucocorticoid/receptor hormones are known to cause apaotosis, in immature
  thymus cells.
  
  TCDD/Ah induced genes result in such oxidative damage, which can also be
  initiated by phytoaxelins.  the resulting reactive mutagenic intermediaries
  also play a role in tumor promotion.
  
  "The endogenous [Ah] ligand is not known.  There are similarities between
  the chemical structures of [exogenous] ligands [tcdd, BaP etc.] and those
  of several representative phytoaxelins.  hence it is tempting to speculate
  that during evolutuion the Ah receptor evolved in animals as part of a
  transducer pathway for detecting significant concentrations of toxic plant
  flavones and providing a beneficial response, ie the induction of enzymes
  specifically needed for detoxifying flavones and compounds of chemically
  related structure."
  
  i guess this all shows the  ying/yang nature of life & homeostasis.
  abundant reactive compounds in the diet, and in the modern world from many
  other sources, set off a chain of reactions that are an attempt to prevent
  oxidative damage, but also cause oxidative damage, including dna damage
  leading to uncontrolled cellular division, ie cancer (that is one of the
  things apoptosis is meant to prevent, read the wonderful article 'cancer,
  how it originates' {also 'cancer, how it spreads'} in the 9/96 special
  issue of _sci. american_, which begions w/ the sentence: "How cancer arises
  is no longer a mystery.").  genes have evolved that induce enzymes to help
  in both ways--donate electrons to stop the cain reaction (i think that's
  right) and induce apoptosis.  the Ah receptor is involved in inducing these
  genes.  once again, exogenous ligands such as tcdd and others are seen to
  inappropriatly mimic a homeostatic mechanism (at biol. relevant low doses
  only, perhaps).  i suppose it's even possible that inapproriate apoptosis
  signals caused by tcdd could lead to, not prevent, uncontrolled cell growth
  (cancer).
  
  
  tony tweedale