In Vitro Inhibition of Human Hepatic and cDNA-Expressed Sulfotransferase Activity with 3-Hydroxybenzo[a]pyrene by Polychlorobiphenylols

摘要: Polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) are two classes of environmentally prevalent pollutants. PAHs formed through the combustion fossil fuels burning organic materials (Dipple 1985). PCBs were first produced industrially in middle last century for their desirable dielectric properties (Erickson 2001) remain environment because continued use, release from waste sites, many congeners slowly degraded. The more lipophilic often found same environmental samples, such as soils sediments, bio-transformed animals by similar pathways (James 2001). Of PAHs, benzo[a]pyrene (BaP) is a well-studied chemical carcinogen, which metabolized cytochrome P-450 (CYP) to variety products These include 3-hydroxybenzo[a]pyrene (3-OH-BaP), major metabolite BaP humans animals, has estrogenic binds hemoglobin (Charles et al. 2000; Sugihara James 2003). Hydroxylated PAH metabolites 3-OH-BaP substrates glucuronidation sulfonation, catalyzed one or UDP-glucuronosyltransferases 3′-phosphoadenosine 5′-phosphosulfate (PAPS)-dependent sulfotransferases (SULTs), respectively 2001). Sulfonation considered detoxification pathway 3-OH-BaP. PCBs have several toxicologic importance, including polychlorobiphenylols (OH-PCBs), vivo CYP-dependent mono-oxygenation Although they slightly hydrophilic than parent PCBs, OH-PCBs eliminated (Klasson-Wehler 1993). People who highly exposed diet typically blood, some bound plasma proteins (Guvenius 2003; Sandau 2000). Several OH-PCB interact with components endocrine system, potentially interfering thyroid hormone estrogen function (Lans 1993; Safe 1994; Schuur 1998). low affinities both α β receptors, strikingly potent inhibitors human sulfotransferase (SULT1E1), sub-nanomolar concentrations that 50% inhibition (IC50) (Kester This suggests may be indirectly increasing estradiol bioavailability target tissues. As well possibly causing toxicity inhibiting sulfonation hormones, inhibited channel catfish intestine (van den Hurk 2002). Sulfonation an important phase II conjugation xenobiotics modulation endogenous compounds steroids, neurotransmitters (Coughtrie One members superfamily cytosolic SULT enzymes catalyze these reactions (Blanchard 2004). SULT1A1, SULT1B1, SULT1E1 phenol expressed liver, SULT1A1 (also known ST1A3) at highest concentration (Honma 2002). SULT1A3 gut but present very adult liver (Richard Genetic polymorphisms SULT1A: G638→A transition leading Arg213→His exchange protein was observed frequency 33.2% Caucasian subjects, 8% Chinese, 29.4% African Americans (Carlini SULT1A1*His (SULT1A1*2) less thermostable SULT1A1*Arg (SULT1A1*1), authors reported SULT1A1*2 variant catalytically active (Ozawa 1998; Raftogianis 1997). Because people frequently coexposed we wished determine if would inhibit (HL) cytosol and, so, whether isozyme selective. We used cDNA-expressed SULT1A1*1, -1A1*2, -1A3, -1B1, 1E1 isozymes, expected use substrate. genotyped HL fractions this study, respect common polymorphic variants, examine possibility affect activity differently. studies conducted series predominantly para-OH-PCBs.