Blockade of alpha-1 adrenergic receptor inhibits hepatic DNA synthesis stimulated by tumor promoters.
Studies with regenerating liver and hepatocyte cultures have shown that the alpha-1 adrenergic receptor (A1AR) is involved in the early events which transmit a mitogenic signal to hepatocytes after 2/3 partial hepatectomy. In this study, we investigated the role of A1AR in DNA synthesis associated with the augmentative hyperplasia stimulated by the xenobiotic hepatic tumor promoters phenobarbital (PB) and alpha-hexachlorocyclohexane (alpha-HCH), and the peroxisome proliferator ciprofibrate. Male F344 rats were treated with each of the three xenobiotics to stimulate hepatic DNA synthesis. When either phenobarbital or alpha-HCH administration was preceded and accompanied by the A1AR antagonist prazosin, DNA synthesis was significantly inhibited, as measured by [3H]thymidine incorporation or 5-bromo-2'-deoxyuridine (BrdU) nuclear labeling index. There was no inhibition of DNA synthesis by prazosin in the ciprofibrate treated group. The inhibition of hepatic DNA synthesis by prazosin was accompanied by non-significant changes in the number of alpha-1 binding sites in the PB and alpha-HCH treated groups, but a significantly reduced number of alpha-1 binding sites in the ciprofibrate treated group. These studies suggest that A1AR is involved in generating the mitogenic signal leading to hepatic DNA synthesis induced by xenobiotic hepatic tumor promoters phenobarbital and alpha-HCH. A1AR is not involved in the mitogenic pathway generated by the peroxisome proliferator ciprofibrate.
Tsai
W H
WH
Department of Pathology, Duke University Medical Center, Durham, NC 27710.
Cruise
J L
JL
Michalopoulos
G K
GK
D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D002994:Clofibrate / Q000031:analogs & derivatives*; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis*; D058607:Fibric Acids; D001556:Hexachlorocyclohexane / Q000494:pharmacology*; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects*; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital / Q000494:pharmacology*; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*
D002273:Carcinogens; D058607:Fibric Acids; D011942:Receptors, Adrenergic, alpha; D002995:Clofibric Acid; D001556:Hexachlorocyclohexane; D004247:DNA; C019304:ciprofibrate; D002994:Clofibrate; D011224:Prazosin; D010634:Phenobarbital