PMID- 8205533
OWN - NLM
STAT- MEDLINE
DCOM- 19940713
LR  - 20231213
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 54
IP  - 12
DP  - 1994 Jun 15
TI  - Colocalized alterations in connexin32 and cytochrome P450IIB1/2 by phenobarbital 
      and related liver tumor promoters.
PG  - 3145-52
AB  - Direct intercellular signal transduction is achieved by the passage of small 
      molecules through gap junctions (GJ). Previous studies in our laboratory showed 
      that the liver tumor promoter phenobarbital (PB) reversibly decreases the 
      abundance of the GJ protein connexin32 (Cx32) in both preneoplastic-altered 
      hepatic foci and centrolobular hepatocytes (M. J. Neveu et al., Cancer Commun., 
      2: 21-31, 1990). Because the inhibitory effects of PB on GJ intercellular 
      communication are prevented by the nonspecific cytochrome P-450 inhibitor 
      SKF-525A (J. E. Klauning, et al., Toxicol. Appl. Pharmacol., 102: 533-563, 1990), 
      we investigated whether alterations in Cx32 are coincident with changes in the 
      major PB-inducible cytochrome P-450, termed b/e or IIB1/2. Immunostaining of 
      liver cryosections from rats fed dietary PB demonstrated that centrolobular 
      hepatocytes that exhibit reduced Cx32 express enhanced cytochrome P450IIB1/2 
      protein. In contrast, no change in the periportal distribution of connexin26 
      immunoreactivity was found in PB-treated rats. In addition, rats were treated 
      with the structurally related barbiturates pentobarbital, amobarbital, barbital, 
      and barbituric acid. We found that the extent of the hepatic lobule occupied by 
      coincident centrolobular alterations in Cx32 and P-450 staining correlates with 
      the ability of the compounds to promote liver oncogenesis. To determine the 
      molecular mechanisms responsible for the modification in Cx32 staining, we 
      examined the mRNA and protein levels of Cx32 and P450IIB1/2 in total-tissue 
      homogenates from PB-treated rats. Northern blotting demonstrated thatdietary PB 
      dramatically induced P-450IIB1 mRNA, but the same RNA samples failed to show 
      alterations in Cx32 steady-state transcripts. Consistent with these findings, the 
      level of Cx32 protein in total liver homogenates did not change in rats 
      chronically fed PB. Examination of Cx32 solubility in 20 mM NaOH demonstrated 
      that PB treatment results in the generation of a NaOH-soluble form of Cx32 (i.e., 
      47 kDa). In addition, trypsinized paraffin-embedded liver sections from 
      PB-treated rats exhibited diffuse cytoplasmic Cx32 staining that was restricted 
      to centrolobular cells. Our results show that PB and related barbiturate tumor 
      promoters reversibly down-regulate punctate Cx32 staining in centrolobular 
      hepatocytes posttranslationally, possibly through modification(s) in the 
      transport, assembly, and/or turnover of GJs.
FAU - Neveu, M J
AU  - Neveu MJ
AD  - McArdle Laboratory for Cancer Research, University of Wisconsin 53706-1599.
FAU - Babcock, K L
AU  - Babcock KL
FAU - Hertzberg, E L
AU  - Hertzberg EL
FAU - Paul, D L
AU  - Paul DL
FAU - Nicholson, B J
AU  - Nicholson BJ
FAU - Pitot, H C
AU  - Pitot HC
LA  - eng
GR  - CA-07175/CA/NCI NIH HHS/United States
GR  - CA-45700/CA/NCI NIH HHS/United States
GR  - ESO-7015/ES/NIEHS NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Barbiturates)
RN  - 0 (Carcinogens)
RN  - 0 (Connexins)
RN  - 0 (RNA, Messenger)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 1.14.- (Steroid Hydroxylases)
RN  - EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases)
RN  - EC 1.14.14.1 (steroid 16-beta-hydroxylase)
RN  - NI40JAQ945 (Tetradecanoylphorbol Acetate)
RN  - YQE403BP4D (Phenobarbital)
SB  - IM
MH  - Animals
MH  - *Aryl Hydrocarbon Hydroxylases
MH  - Barbiturates/pharmacology
MH  - Carcinogens/*pharmacology
MH  - Cell Communication/drug effects/physiology
MH  - Connexins/*metabolism/physiology
MH  - Cytochrome P-450 Enzyme System/biosynthesis/*metabolism/physiology
MH  - Enzyme Induction
MH  - Gap Junctions/drug effects/physiology
MH  - Immunoblotting
MH  - Liver/*drug effects/*metabolism
MH  - Liver Neoplasms, Experimental/chemically induced/enzymology/metabolism
MH  - Male
MH  - Phenobarbital/*pharmacology
MH  - Protein Processing, Post-Translational/drug effects
MH  - RNA, Messenger/metabolism
MH  - Rats
MH  - Rats, Inbred F344
MH  - Steroid Hydroxylases/biosynthesis/*metabolism/physiology
MH  - Tetradecanoylphorbol Acetate/pharmacology
MH  - Gap Junction beta-1 Protein
EDAT- 1994/06/15 00:00
MHDA- 1994/06/15 00:01
CRDT- 1994/06/15 00:00
PHST- 1994/06/15 00:00 [pubmed]
PHST- 1994/06/15 00:01 [medline]
PHST- 1994/06/15 00:00 [entrez]
PST - ppublish
SO  - Cancer Res. 1994 Jun 15;54(12):3145-52.