Abstract
DDT and lindane are highly toxic organochlorine pesticides and posing adverse effects on the environment and public health due to their frequent usage in developing countries. ABCC4/MRP4 is an organic anion transporter that mediates cellular efflux of a wide range of exogenous and endogenous compounds such as cyclic nucleotides and anti-cancer drugs; however, it remains unclear whether ABCC4 and its orthologs function in the detoxification of organochlorine pesticides. Here, we demonstrated the roles of zebrafish Abcc4 in cellular efflux of DDT and lindane. Zebrafish abcc4 was maternally expressed in the oocytes and its transcripts were detected in the lens, pancreas, gills, liver, intestine and bladder of developing embryos and in adult tissues examined. DDT and lindane were able to induce the expression of abcc4 gene and overexpression of Abcc4 significantly decreased the cytotoxicity and accumulation of DDT and lindane in LLC-PK1 cells and developing embryos. In contrast, overexpression of an Abcc4-G1188D mutant abolished its transporter function without effects on its substrate binding activity, and sensitized LLC-PK1 cells and developing embryos to toxic pesticides. Moreover, glutathione (GSH) was involved in the efflux of cellular pesticides and ATPase activity in developing embryos can be induced by DDT or lindane. Thus, zebrafish Abcc4 plays crucial roles in cellular efflux of organochlorine pesticides and can be used a potential molecular marker for the monitor of DDT and lindane contamination in the aquatic environment.
Highlights
Multidrug resistance-associated proteins (MRPs) belong to the subfamily C of ATP binding cassette (ABC) superfamily, which are the largest and most ancient transmembrane proteins found in all organisms from prokaryotes to mammals [1]
Zebrafish Abcc4 contains functional domains and critical residues as defined in human ABCC4 and these domains include two transmembrane-spanning domains (TMD), each consisting of six transmembrane helices (TMH) and two nucleotide binding domains (NBDs) with walker A, ABC signature and walker B (Fig.S2)
Three potential N-glycosylation sites were predicted in the Cterminal membrane spanning domain (N751, N756 and N762) between TMH7 and TMH8 of zebrafish Abcc4
Summary
Multidrug resistance-associated proteins (MRPs) belong to the subfamily C of ATP binding cassette (ABC) superfamily, which are the largest and most ancient transmembrane proteins found in all organisms from prokaryotes to mammals [1]. MRPs are capable of transporting a wide array of toxic compounds including heavy metals [6], food components and drugs [7], and other xenobiotics These efflux transporters have exhibited essential functions in tissue defense and can protect vital body structures, such as brain, cerebrospinal fluid, testis and fetus, against the action of toxins [8]. ABCC4/MRP4 is localized to either the apical membrane of human kidney proximal tubules [9], or the basolateral membrane of hepatocytes [10] and pancreatic ductular epithelial cells [11] It serves as an organic anion transporter and can mediate the efflux of glutathione-, glucosiduronide- and sulfateconjugated substrates [12, 13], including both endogenous compounds such as cyclic nucleotides, nucleoside analogs, bile acids and steroids conjugate [14, 15], and exogenous compounds such as anti-cancer and anti-viral drugs [16]. In the blood-brain barrier, bloodcerebrospinal fluid barrier and stomach, ABCC4 can limit the penetration and accumulation of drugs and toxicants and has exhibited functions in tissue defense [18, 19]
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