Interactions of pharmaceuticals and other xenobiotics on key detoxification mechanisms and cytoskeleton in Poeciliopsis lucida hepatocellular carcinoma, PLHC-1 cell line.
Fish are exposed to chemicals, including pharmaceuticals, in their natural habitat. This study focuses on effects of chemicals, including nine classes of pharmaceuticals, on key detoxification mechanisms in a fish liver cell-line (PLHC-1). Chemical interactions were investigated on efflux pumps, P-glycoprotein (Pgp) and multidrug resistance associated proteins (MRP1/MRP2), and on biotransformation enzymes, cytochrome P450 (CYP1A/CYP3A). Diclofenac and troleandomycin inhibited efflux activities, whereas ethinylestradiol activated efflux function. Exposure to troleandomycin and β-naphthoflavone induced MRP2 mRNA levels, but no effects were seen on MRP1 or Pgp expressions. Inhibition of CYP1A activities were seen in cells exposed to α-naphthoflavone, β-naphthoflavone, clotrimazole, nocodazole, ketoconazole, omeprazole, ethinylestradiol, lithocholic acid, rifampicin and troleandomycin. Exposure to fulvestrant, clotrimazole and nocodazole resulted in induction of CYP1A mRNA levels. Although, exposure to nocodazole resulted in disassembled microtubules. A CYP3A-like cDNA sequence was isolated from PLHC-1, but basal expression and activities were low and the gene was not responsive to prototypical CYP3A inducers. Exposure to ibuprofen, lithocholic acid and omeprazole resulted in fragmentation of microtubules. This study revealed multiple interactions on key detoxification systems, which illustrates the importance of study effects on regulation combined with functional studies to provide a better picture of the dynamics of the chemical defense system.
Department of Biological and Environmental Sciences, University of Gothenburg, Box 463, SE-405 30 Göteborg, Sweden.
Britt
B
Wassmur
Johanna
J
Gräns
Elisabeth
E
Norström
Margareta
M
Wallin
Malin C
MC
Celander
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004347:Drug Interactions; D005399:Fishes; D008658:Inactivation, Metabolic; D008113:Liver Neoplasms / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D004364:Pharmaceutical Preparations; D012333:RNA, Messenger / Q000378:metabolism; D015262:Xenobiotics / Q000494:pharmacology*
D018435:ATP Binding Cassette Transporter, Subfamily B; D019363:Cytochrome P-450 CYP1A1; D051544:Cytochrome P-450 CYP3A; D018076:DNA, Complementary; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D004364:Pharmaceutical Preparations; D012333:RNA, Messenger; D015262:Xenobiotics