Polychlorinated biphenyls as inducers of hepatic microsomal enzymes: Structure-activity rules

Abstract

A number of highly purified polychlorinated biphenyl (PCB) isomers and congeners were synthesized and administered to male Wistar rats at dosage levels of 30 and 150 mumol . kg-1. The effects of this in vivo treatment on the drug-metabolizing enzymes were determined by measuring the microsomal benzo[a]pyrene (B[a]P) hydroxylase, dimethylaminoantipyrine (DMAP) N-demethylase and NADPH-cytochrome c reductase enzyme activities, the cytochrome b5 content and the relative peak intensities and spectral shifts of the reduced microsomal cytochrome P-450 CO and ethylisocyanide (EIC) binding difference spectra. The results were compared to the effects of administering phenobarbitone (PB), 3-methylcholanthrene (MC) and PB plus MC (coadministered) to the test animals. The synthetic PCB congeners used in this study included 3,4,4',5-tetrachlorobiphenyl (TCBP-1), 2,3',4,4'-tetrachlorobiphenyl (TCBP-2), 2,3',4,4',5'-pentachlorobiphenyl (PCBP-1), 2,3,4,-4',5-pentachlorobiphenyl (PCBP-2), 2,3,3',4,4',5-hexachlorobiphenyl (HCBP-1) 2,3',4',5,6-hexachlorobiphenyl (HCBP-2), 2,3,3',5,5',6-hexachlorobiphenyl (HCBP-3), 2,2',3,5,5',6-hexachlorobiphenyl (HCBP-4) and 2,3,3',4,5,5'-hexachlorobiphenyl (HCBP-5) and were used to reappraise the structure-activity rules for PCBs as hepatic microsomal enzyme inducers. The results suggested that (a) PCBs which induce MC or mixed-type activity must be substituted at both para positions, at least two meta positions but not necessarily on the same phenyl ring and can also contain one ortho chloro substituent; (b) due to the considerable structural diversity of the PB-type inducers the rules for induction of this activity by PCB congeners are not readily defined.

Metabolic activation of PCBs to carcinogens in vivo—A review

“…In general, the fewer halogens, the more rapid the metabolic transformation. In other words, PCBs are not only efficacious inducers of xenobiotic metabolism (Parkinson et al, 1980), but may also become substrates for the induced enzymes. Associated with their metabolism may be the metabolic activation to electrophiles and the ensuing reaction with cellular substituents, such as proteins, lipids, and DNA.…”

Environmental occurrence, abundance, and potential toxicity of polychlorinated biphenyl congeners: considerations for a congener-specific analysis.

“…The moderately chlorinated isomer groups also contain most of the mixedfunction oxidase (MFO)-inducing congeners. Two of the three pure 3-MC-type inducers and all but two of the mixed-type inducers are penta-, hexa-, or heptachlorobiphenyls (17)(18)(19)(20)(21)(22)(23)(24). The more highly chlorinated congeners are generally less available to organisms both because they are more tightly bound with soils and sediments and because they usually are present in lower quantities in the environment.…”

Polychlorinated biphenyls and polybrominated biphenyls

“…A study in which wildtype and knockout mouse strains were exposed in utero and by lactation to a complex mixture of PCBs showed that mice with poor-affinity AhR and lacking CYP1A2 (Cyp1a2 (-/-) knockout) had higher concentrations of congeners with no or one ortho chlorine in tissues than mice with high-affinity AhR and CYP1A2 (Cyp1a2 (+/+) wildtype), consistent with low metabolism of these PCB congeners in the knockout mice (Curran et al, 2011). PCBs with two or more ortho chlorines and at least one para chlorine interact with rat and human CAR and induce CYP2B family isoforms, including CYP2B1 and CYP2B6 in a similar manner to the classic inducer, phenobarbital (Parkinson et al, 1980;Al-Salman & Plant, 2012). Some PCBs with two or more ortho chlorines have been shown to bind to the human and rat PXR and to human CAR, resulting in upregulation of CYP3A4 (Waller et al, 1996;Petersen et al, 2007;Al-Salman & Plant 2012).…”

“…The reason that continuous exposure to certain PCB congeners can affect rate and extent of metabolism is that such exposure can result in upregulation of expression of enzymes that biotransform PCBs, through receptor-mediated processes. PCBs that bind the aryl hydrocarbon receptor (AhR) (see Section 4.3.1) are known to induce CYP isoforms in the 1 family (CYP1A1, CYP1A2 and CYP1B1) as well as epoxide hydrolase, some isoforms of uridine diphosphate-glucuronosyltransferase (UGT) and glutathione S-transferase (GST) (Parkinson et al, 1980;1983). PCBs that bind the nuclears receptors, the pregnane-X receptor (PXR) and the constitutive androstane receptor (CAR) have been shown to induce CYP3A4 and CYP2B isoforms (Petersen et al, 2007;Al-Salman & Plant, 2012).…”