Rd. White et al., METABOLISM OF THE ARYL-HYDROCARBON RECEPTOR AGONIST 3,3',4,4'TETRACHLOROBIPHENYL BY THE MARINE FISH SCUP (STENOTOMUS CHRYSOPS) IN-VIVO AND IN-VITRO, Drug metabolism and disposition, 25(5), 1997, pp. 564-572
The metabolism of the polychlorinated biphenyl congener 3,3',4,4'-tetr
achlorobiphenyl (TCB) was examined in vitro and in vivo in the marine
fish scup (Stenotomus chrysops). Untreated soup liver microsomes catal
yzed metabolism of TCB with an estimated K-M of 0.7 mu M, at a rate le
ss than or equal to 0.13 pmol/min/mg. Metabolism was NADPH-dependent a
nd inhibited by cytochrome c and CO, indicating cytochrome P450 (CYP)
involvement. alpha-Naphthoflavone strongly inhibited microsomal TCB me
tabolism, and treatment of fish with CYP1A inducers increased the rate
s by similar to 2-fold, suggesting involvement of CYP1A. Soup were inj
ected intraperitoneally with 0.1 or 5 mg TCB/kg and sampled on days 1-
16 after treatment (after 3 days without food at each sampling). Conce
ntrations of unmetabolized TCB in liver peaked on day 5 in low dose fi
sh and on day 12 in high dose fish. In both groups the TCB content in
liver had declined 60% or more by day 16, suggesting depuration or red
istribution from the liver. GC and MS revealed TCB and TCB metabolites
in bile within 24 hr of treatment. The concentrations of TCB and meta
bolites in bile peaked at the same time that TCB concentrations peaked
in the liver. The major metabolites were 5-hydroxy-3,3',4,4'-TCB (5-O
H-TCB) and 4-hydroxy-3,3',5,4'-TCB (4-OH-TCB); 2-hydroxy-3,3',4,4'-TCB
and 6-hydroxy-3,3',4,4'-TCB were minor metabolites, Animals given the
high dose had much less 5-OH-TCB and much more parent TCB in bile tha
n did fish given the low dose, Amounts of 4-OH-TCB in bile did not dif
fer between doses. The reduced excretion of 5-OH-TCB coincided with a
suppression of CYP1A in fish given the high dose, that did not occur i
n low dose fish, consistent with an involvement of CYP1A in TCB metabo
lism and particularly in formation of 5-OH-TCB. This study provides th
e first direct demonstration of 3,3',4,4'-TCB metabolism by fish. Data
also indicate that these fish are able to eliminate TCB both as paren
t compound and as metabolites, despite a very slow rate of metabolism
in vitro.