{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T11:58:33Z","timestamp":1774439913459,"version":"3.50.1"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":6332,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1998,5]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>Cyclic adenosine monophosphate (cAMP) has been shown to modulate apoptosis. To evaluate the role of cAMP in bile acid-induced hepatocyte apoptosis, we studied the effect of agents that increase cAMP on the induction of apoptosis by glycochenodeoxycholate (GCDC) in cultured rat hepatocytes. GCDC induced apoptosis in 26.5% \u00b1 1.1% of hepatocytes within 2 hours. Twenty-minute pretreatment of hepatocytes with 100 \u03bcmol\/L 8-(4-chlorothiophenyl) cAMP (CP-cAMP) resulted in a reduction in the amount of apoptosis to 35.2% \u00b1 3.8% of that seen in hepatocytes treated with GCDC alone. Other agents that increase intracellular cAMP, including dibutyryl cAMP (100 \u03bcmol\/L), glucagon (200 nmol\/L), and a combination of forskolin (20 \u03bcmol\/L) and 3-isobutyl-1-methylxanthine (20 \u03bcmol\/L), also inhibited GCDC-induced apoptosis to a similar extent. Pretreatment with the protein kinase A (PKA) inhibitor, KT5720, prevented the protective effect of CP-cAMP and inhibited CP-cAMP-induced activation of PKA activity. Inhibitors of phosphatidylinositol 3-kinase (PI3K), wortmannin (50 nmol\/L), or Ly 294002 (20 \u03bcmol\/L) also prevented the cytoprotective effect of cAMP. PI3K assays confirmed that wortmannin (50 nmol\/L) inhibited PI3K activity, while CP-cAMP had no effect on the activity of this lipid kinase. GCDC increased mitogen-activated protein kinase (MAPK) activity, but had no effect on stress-activated protein kinase (SAPK) activity in hepatocytes. cAMP decreased basal and GCDC-induced MAPK activity and increased SAPK activity. The MAPK kinase inhibitor, PD 98059, inhibited both GCDC-mediated MAPK activation and GCDC-induced apoptosis. In conclusion: 1) agents that increase intracellular cAMP protect against hepatocyte apoptosis induced by hydrophobic bile acids; 2) activation of MAPK by GCDC may be involved in bile acid-induced apoptosis; and 3) cAMP-mediated cytoprotection against bile acid-induced apoptosis appears to involve PKA, MAPK, and PI3K.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.510270519","type":"journal-article","created":{"date-parts":[[2004,7,27]],"date-time":"2004-07-27T23:52:40Z","timestamp":1090972360000},"page":"1324-1331","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":97,"title":["Cyclic adenosine monophosphate-mediated protection against bile acid-induced apoptosis in cultured rat hepatocytes"],"prefix":"10.1097","volume":"27","author":[{"given":"Cynthia R.L.","family":"Webster","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sawkat M.","family":"Anwer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"BIB1","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/0968-0004(94)90170-8","volume":"19","author":"Martin","year":"1994","journal-title":"Trends Biol Sci"},{"key":"BIB2","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1006\/taap.1994.1195","volume":"128","author":"Corcoron","year":"1994","journal-title":"Toxicol Appl Pharmacol"},{"key":"BIB3","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1126\/science.7878464","volume":"267","author":"Thompson","year":"1995","journal-title":"Science"},{"key":"BIB4","first-page":"1725","volume":"21","author":"Patel","year":"1995","journal-title":"Hepatology"},{"key":"BIB5","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1097\/00007890-199559040-00031","volume":"59","author":"Krams","year":"1995","journal-title":"Transplantation"},{"key":"BIB6","doi-asserted-by":"crossref","first-page":"2183","DOI":"10.1172\/JCI117579","volume":"94","author":"Patel","year":"1994","journal-title":"J Clin Invest"},{"key":"BIB7","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1172\/JCI116546","volume":"92","author":"Spivey","year":"1993","journal-title":"J Clin Invest"},{"key":"BIB8","first-page":"83","volume-title":"Pediatric Cholestasis: Novel Approaches to Treatment","author":"Schoelmerich","year":"1992","unstructured":"Mechanisms of bile salt toxicity. 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