PMID- 22815834 OWN - NLM STAT- MEDLINE DCOM- 20130321 LR - 20220316 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 7 IP - 7 DP - 2012 TI - Effects of hypoxia exposure on hepatic cytochrome P450 1A (CYP1A) expression in Atlantic croaker: molecular mechanisms of CYP1A down-regulation. PG - e40825 LID - 10.1371/journal.pone.0040825 [doi] LID - e40825 AB - Hypoxia-inducible factor-alpha (HIF-alpha) and cytochrome P450 1A (CYP1A) are biomarkers of environmental exposure to hypoxia and organic xenobiotic chemicals that act through the aryl hydrocarbon receptor, respectively. Many aquatic environments heavily contaminated with organic chemicals, such as harbors, are also hypoxic. Recently, we and other scientists reported HIF-alpha genes are upregulated by hypoxia exposure in aquatic organisms, but the molecular mechanisms of hypoxia regulation of CYP1A expression have not been investigated in teleost fishes. As a first step in understanding the molecular mechanisms of hypoxia modulation of CYP1A expression in fish, we characterized CYP1A cDNA from croaker liver. Hypoxia exposure (dissolved oxygen, DO: 1.7 mg/L for 2 to 4 weeks) caused significant decreases in hepatic CYP1A mRNA and protein levels compared to CYP1A levels in fish held in normoxic conditions. In vivo studies showed that the nitric oxide (NO)-donor, S-nitroso-N-acetyl-DL-penicillamine, significantly decreased CYP1A expression in croaker livers, whereas the competitive inhibitor of NO synthase (NOS), N(omega)-nitro-L-arginine methyl ester, restored CYP1A mRNA and protein levels in hypoxia-exposed (1.7 mg DO/L for 4 weeks) fish. In vivo hypoxia exposure also markedly increased interleukin-1beta (IL-1beta, a cytokine), HIF-2alpha mRNA and endothelial NOS (eNOS) protein levels in croaker livers. Pharmacological treatment with vitamin E, an antioxidant, lowered the IL-1beta, HIF-2alpha mRNA and eNOS protein levels in hypoxia-exposed fish and completely reversed the down-regulation of hepatic CYP1A mRNA and protein levels in response to hypoxia exposure. These results suggest that hypoxia-induced down-regulation of CYP1A is due to alterations of NO and oxidant status, and cellular IL-1beta and HIF-alpha levels. Moreover, the present study provides the first evidence of a role for antioxidants in hepatic eNOS and IL-1beta regulation in aquatic vertebrates during hypoxic stress. FAU - Rahman, Md Saydur AU - Rahman MS AD - Marine Science Institute, University of Texas at Austin, Port Aransas, Texas, United States of America. rahman@mail.utexas.edu FAU - Thomas, Peter AU - Thomas P LA - eng SI - GENBANK/JQ622219 SI - GENBANK/JQ622220 PT - Journal Article PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20120716 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Antioxidants) RN - 0 (RNA, Messenger) RN - 31C4KY9ESH (Nitric Oxide) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type III) SB - IM MH - Animals MH - Antioxidants/pharmacology MH - Atlantic Ocean MH - Blotting, Western MH - Cytochrome P-450 Enzyme System/*genetics/metabolism MH - Down-Regulation/drug effects/*genetics MH - Gene Expression Profiling MH - *Gene Expression Regulation, Enzymologic MH - Hypoxia/*enzymology/*genetics MH - Immunohistochemistry MH - Liver/drug effects/*enzymology MH - Models, Biological MH - Molecular Sequence Data MH - Nitric Oxide/pharmacology MH - Nitric Oxide Synthase Type III/metabolism MH - Organ Specificity/drug effects/genetics MH - Perciformes/*genetics MH - Protein Transport/drug effects/genetics MH - RNA, Messenger/genetics/metabolism MH - Reverse Transcriptase Polymerase Chain Reaction MH - Time Factors MH - Tissue Distribution/drug effects/genetics PMC - PMC3397942 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2012/07/21 06:00 MHDA- 2013/03/22 06:00 PMCR- 2012/07/16 CRDT- 2012/07/21 06:00 PHST- 2012/04/17 00:00 [received] PHST- 2012/06/13 00:00 [accepted] PHST- 2012/07/21 06:00 [entrez] PHST- 2012/07/21 06:00 [pubmed] PHST- 2013/03/22 06:00 [medline] PHST- 2012/07/16 00:00 [pmc-release] AID - PONE-D-12-11055 [pii] AID - 10.1371/journal.pone.0040825 [doi] PST - ppublish SO - PLoS One. 2012;7(7):e40825. doi: 10.1371/journal.pone.0040825. Epub 2012 Jul 16.