Chiral effects in the induction of drug-metabolizing enzymes using synthetic atropisomers of polychlorinated biphenyls (PCBs).
Atropisomers of the polychlorinated biphenyls 2,2',3,4,4',6-hexachlorobiphenyl (II) and 2,2',3,3',4,4',6,6'-octachlorobiphenyl (III), stable to racemization under physiological conditions, were administered to immature male Sprague-Dawley rats. The racemic hexachlorobiphenyl (II) was found to be a potent (phenobarbital-type) inducer, whereas (+)-II and (-)-II, administered at 100 mumol/kg, showed clearly differing potencies as inducers with (+)-II enhancing aminopyrine N-demethylase, aldrin epoxidase and cytochrome P-450 content more potently than (-)-II. In contrast, the racemic octachlorobiphenyl (III) and its individual enantiomers were only weak phenobarbital-type inducers of cytochrome P-450, and the enantiomers of III were equally (weakly) potent. Separate studies conducted to investigate pharmacokinetic influences on the differential potency of the enantiomers of II showed that after 5 days the concentration of (+)-II in the liver was twice as high as that of its antipode. Therefore, enantioselectivity in disposition as well as in recognition may be responsible for the differential potency seen.
Püttmann
M
M
Institute of Toxicology, University of Mainz, FRG.
Mannschreck
A
A
Oesch
F
F
Robertson
L
L
D000818:Animals; D004790:Enzyme Induction / Q000187:drug effects*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C059159:2,2',3,3',4,4',6,6'-octachlorobiphenyl; C059158:2,2',3,4,4',6-hexachlorobiphenyl; D011078:Polychlorinated Biphenyls