title: Toxicokinetics of dioxins and other organochlorine compounds in Japanese people: association with hepatic CYP1A2 expression levels.
abstract: Concentrations of persistent organochlorine compounds (OCs) including polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) in the liver and adipose tissue of Japanese cadavers were measured, and their toxicokinetics were examined in association with hepatic cytochrome P450 (CYP) 1A protein expression levels. Total 2,3,7,8-tetrachlorodibenzo-p-dioxin toxic equivalents (TEQs) were 66±74 and 65±57 pg/g lipid weight (mean±S.D.) in the liver and adipose tissue, respectively. Total PCBs (sum of 62 congeners targeted), p,p'-dichlorodiphenyl-dichloroethylene (p,p'-DDE) and β-hexachlorocyclohexane (β-HCH) were detected at concentrations over 1 μg/g lipid in both tissues of some specimens. For most of the dioxin-like congeners, total PCBs, p,p'-DDE, oxychlordane, α- and β-HCH, hexachlorobenzene (HCB), and tris(4-chlorophenyl)methane (TCPMe), age-dependent increases in concentrations were found in the adipose tissue of males. No such age-dependent trend was observed in the liver, suggesting that there are different mechanisms underlying the hepatic concentrations of OCs. Immunoblot analyses indicated detectable expression of hepatic CYP1A2 protein, whereas no CYP1A1 protein was detected. The CYP1A2 expression levels were positively correlated with concentrations (on wet weight basis) of 2,3,4,7,8-P₅CDF, the dominant TEQ-contributed congeners in the liver, indicating the induction of this CYP. Hepatic CYP1A2 protein levels were strongly correlated with the liver to adipose concentration (L/A) ratios of PCDD/F congeners with more than 5 chlorine atoms. Together with higher concentrations of the congeners in the liver than in the adipose tissue, the observation on L/A ratios of highly chlorinated PCDD/Fs suggests that induced hepatic CYP1A2 protein is involved in their sequestration in this human population, as observed in model animals (rodents). Nonetheless, the magnitude of hepatic sequestration (L/A ratio) of PCDD/Fs in this human population was lower than in other mammals and birds, reported previously. This study emphasizes the fact that toxicokinetics of some OCs can be affected at least partly by CYP1A2 protein levels in humans. For the extrapolation of their toxicokinetics from model animals to humans, knowledge on the induction and sequestration potencies of CYP1A is necessary.
authors: Center for Marine Environmental Studies-CMES, Ehime University, Bunkyo-cho 2-5, Matsuyama 790-8577, Japan.
authors: Michio X
authors: MX
authors: Watanabe
authors: Tatsuya
authors: T
authors: Kunisue
authors: Norifumi
authors: N
authors: Ueda
authors: Masato
authors: M
authors: Nose
authors: Shinsuke
authors: S
authors: Tanabe
authors: Hisato
authors: H
authors: Iwata
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001572:Benzofurans / Q000633:toxicity; D002706:Chlordan / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000072338:Dibenzofurans, Polychlorinated; D003633:Dichlorodiphenyl Dichloroethylene / Q000378:metabolism / Q000633:toxicity; D004147:Dioxins / Q000378:metabolism / Q000633:toxicity*; D004781:Environmental Exposure / Q000032:analysis* / Q000706:statistics & numerical data; D004785:Environmental Pollutants / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D006581:Hexachlorobenzene / Q000378:metabolism; D001556:Hexachlorocyclohexane / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000378:metabolism / Q000633:toxicity*; D007564:Japan; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011078:Polychlorinated Biphenyls / Q000378:metabolism / Q000633:toxicity; D000072317:Polychlorinated Dibenzodioxins / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity
chemical_list: D001572:Benzofurans; D000072338:Dibenzofurans, Polychlorinated; D004147:Dioxins; D004785:Environmental Pollutants; D006843:Hydrocarbons, Chlorinated; D000072317:Polychlorinated Dibenzodioxins; D002706:Chlordan; C008743:oxychlordane; D003633:Dichlorodiphenyl Dichloroethylene; D006581:Hexachlorobenzene; D001556:Hexachlorocyclohexane; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; C020887:dibenzo(1,4)dioxin; C023888:beta-hexachlorocyclohexane