In vitro-in vivo extrapolation of hepatic and gastrointestinal biotransformation rates of hydrophobic chemicals in rainbow trout
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| Authors: | Saunders, LJ; Fitzsimmons, PN; Nichols, JW; Gobas, FAPC |
| Year: | 2020 |
| Journal: | Aquat. Toxicol. 228 Article Link (DOI) PubMed |
| Title: | In vitro-in vivo extrapolation of hepatic and gastrointestinal biotransformation rates of hydrophobic chemicals in rainbow trout |
| Abstract: | Hepatic in vitro biotransformation assays, in combination with in vitro-in vivo extrapolation (IVIVE) and bioaccumulation modeling, can be used to support regulatory bioaccumulation assessments. In most applications, however, these methods ignore the possibility of extrahepatic metabolism. Here we evaluated intestinal biotransformation in rainbow trout using 59 fractions prepared from the upper intestinal (GIT) epithelium. Measured levels of activity determined using standard substrates for phase I and phase II biotransformation enzymes were within 2-fold of activities measured in hepatic 59 fractions. In vitro intrinsic clearance rates for 2-ethylhexyl-4-methoxycinnamate (EHMC; an organic sunscreen agent) and two polycyclic aromatic hydrocarbons (pyrene [PYR] and benzo(a)pyrene [BAP]) were significantly higher in liver 59 fractions than in GIT 59 fractions. For octocrylene (OCT; a second sunscreen agent), however, in vitro intrinsic clearance rates were higher in GIT 59 fractions compared to liver 59 fractions. An existing 'liver only' IVIVE model was expanded to consider biotransformation in both the liver and GIT. Relevant IVIVE scaling factors were developed by morphological, histological, and biochemical evaluation of trout intestines. For chemicals biotransformed at higher rates by hepatic 59 fractions (i.e., BAP, PYR, EHMC), the 'liver & GIT' model yielded whole-body biotransformation rate |
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