PMID- 9299183
OWN - NLM
STAT- MEDLINE
DCOM- 19971023
LR  - 20190909
IS  - 0272-0590 (Print)
IS  - 0272-0590 (Linking)
VI  - 38
IP  - 2
DP  - 1997 Aug
TI  - Perturbation of the mitosis/apoptosis balance: a fundamental mechanism in 
      toxicology.
PG  - 107-15
AB  - Perturbations of the balance between cell gain via mitosis and cell loss by 
      apoptosis play a pivotal role in mediating and modifying the action of 
      carcinogens and other toxicants in tissues such as liver, brain, the immune 
      system, the gastrointestinal tract, and the reproductive organs. Apoptosis 
      describes a highly conserved morphology associated with the death of many 
      different cell types from diverse tissues. This symposium focused on induced 
      changes in this critical balance as a key mechanism of action of a variety of 
      diverse toxicants. In the colon, the "toxicology" of 5 fluorouracil (5FU) is 
      entirely dependent on p53, since p53 knockouts lose the pathology of 5FU damage. 
      Presumably, this is because DNA damage is not detected and there is no cell cycle 
      arrest. In the testes, testicular germ cell survival is mediated by adjacent 
      Sertoli cells via the Fas ligand (FasL)-Fas receptor (Fas) system. This system 
      appears to mediate germ cell apoptosis after exposure to testicular toxicants 
      such as the phthalate, mono(2-ethylhexyl) phthalate (MEHP). Interestingly, MEHP 
      is a member of the peroxisome proliferator (PP) class of nongenotoxic 
      carcinogens. PPs perturb both hepatocyte apoptosis and mitosis. This suppression 
      of apoptosis occurs via activation of the peroxisome proliferator-activated 
      receptor alpha (PPARalpha), providing a paradigm for the regulation of liver 
      growth via activation of nuclear receptors. Similarly, the toxicological effects 
      of dioxins are mediated via the Ah receptor (AHR), another ligand-activated 
      nuclear receptor. This receptor upregulates a variety of genes (the Ah gene 
      battery) associated with the toxicology of dioxins. Taken together, the data 
      presented in this symposium illustrate to the toxicologist the need to quantitate 
      and interpret modulations in apoptosis alongside more conventional assessments of 
      S-phase. Although the toxicant may initiate cell damage, genes like Bcl-2, p53, 
      Fas, PPARalpha, and AHR are final arbiters of the choice between death, survival, 
      and proliferation.
FAU - Roberts, R A
AU  - Roberts RA
AD  - Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, SK10 4TJ, 
      United Kingdom.
FAU - Nebert, D W
AU  - Nebert DW
FAU - Hickman, J A
AU  - Hickman JA
FAU - Richburg, J H
AU  - Richburg JH
FAU - Goldsworthy, T L
AU  - Goldsworthy TL
LA  - eng
PT  - Journal Article
PT  - Review
PL  - United States
TA  - Fundam Appl Toxicol
JT  - Fundamental and applied toxicology : official journal of the Society of 
      Toxicology
JID - 8200838
SB  - IM
MH  - Animals
MH  - Apoptosis/*drug effects
MH  - Humans
MH  - Mitosis/*drug effects
MH  - *Toxicology
RF  - 44
EDAT- 1997/08/01 00:00
MHDA- 1997/09/23 00:01
CRDT- 1997/08/01 00:00
PHST- 1997/08/01 00:00 [pubmed]
PHST- 1997/09/23 00:01 [medline]
PHST- 1997/08/01 00:00 [entrez]
AID - S0272059097923319 [pii]
AID - 10.1006/faat.1997.2331 [doi]
PST - ppublish
SO  - Fundam Appl Toxicol. 1997 Aug;38(2):107-15. doi: 10.1006/faat.1997.2331.