Sulfation of Lower Chlorinated Polychlorinated Biphenyls Increases Their Affinity for the Major Drug-Binding Sites of Human Serum Albumin

Abstract

The disposition of toxicants is often affected by their binding to serum proteins, of which the most abundant in humans is serum albumin (HSA). There is increasing interest in the toxicities of environmentally persistent polychlorinated biphenyls (PCBs) with lower numbers of chlorine atoms (LC-PCBs) due to their presence in both indoor and outdoor air. PCB sulfates derived from metabolic hydroxylation and sulfation of LC-PCBs have been implicated in endocrine disruption due to high affinity-binding to the thyroxine-carrying protein, transthyretin. Interactions of these sulfated metabolites of LC-PCBs with HSA, however, have not been previously explored. We have now determined the relative HSA-binding affinities for a group of LC-PCBs and their hydroxylated and sulfated derivatives by selective displacement of the fluorescent probes 5-dimethylamino-1-naphthalenesulfonamide and dansyl--proline from the two major drug-binding sites on HSA (previously designated as Site I and Site II). Values for half-maximal displacement of the probes indicated that the relative binding affinities were generally PCB sulfate ≥ OH-PCB > PCB, although this affinity was site- and congener-selective. Moreover, specificity for Site II increased as the numbers of chlorine atoms increased. Thus, hydroxylation and sulfation of LC-PCBs result in selective interactions with HSA which may affect their overall retention and toxicity.

Identification of a sulfate metabolite of PCB 11 in human serum

“…Similarly, more research is required to expand our current knowledge about potential bioactivities associated with these sulfate metabolites. Previous studies have clearly indicated the potential of PCB sulfates to interact with two major serum transport proteins, albumin (Rodriguez et al 2016) and TTR (Grimm et al 2013, 2015c) in vitro . Binding affinities to both proteins suggest potential mechanisms for the retention and inter-tissue transport of PCB metabolites.…”

Enantioselective Partitioning of Polychlorinated Biphenyls in a HepG2 Cell Culture System: Experimental and Modeling Results

“…Cell culture media and cell pellets were extracted and analyzed for PCB metabolites using targeted and untargeted approaches ( Similarly, an in vitro study showed that the binding affinity of PCBs for binding site Ⅱ of albumin, the major protein in FBS, increases with an increase in the number of chlorine atoms. 52 The PCB mass ratios between cell pellets : media : dishes were 1 : 4.9 : 0.54 for pentachlorinated congeners and : 8.6 : 0.37 for hexachlorinated congeners, respectively. These ratios are comparable to earlier studies.…”

The potential disruption of estrogen and androgen homeostasis and adipocyte differentiation by metabolites of common airborne polychlorinated biphenyls

“…For example, DHEA-sulfate binds to human serum albumin with high affinity and has a halflife of 7-10 hours, while DHEA binds with much lower affinity and has a half-life of 15-30 minutes [375]. By analogy, OH-PCBs and PCB sulfates also bind with high affinity to serum proteins such as human serum albumin [42] and transthyretin [36,376].…”

“…The high volatility of the LC-PCBs leads to their presence in indoor air (especially older buildings) [9-11, 40, 41]. The PCB metabolites consist of hydroxylated and sulfated metabolites [35], but these metabolites are also able to elicit genotoxic effects that are produced from further metabolism into quinones and other reactive species [7,34,35,41,42].…”

“…Polychlorinated biphenyls are persistent toxicants that are associated with the development of many adverse health effects such as obesity, diabetes, cancer, neurotoxicity, thyroid dysfunction, and more [37,42,61,305]. They were often used in the 20 th century because of their chemical stability and physical properties [31,306].…”