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S Safe

Publications and source records attributed to S Safe.

At least 235 records · Page 13Linked to original sources
PubMed1985

PCBs: structure-function relationships and mechanism of action.

Numerous reports have illustrated the versatility of polychlorinated biphenyls (PCBs) and related halogenated aromatics as inducers of drug-metabolizing enzymes and the activity of individual compounds are remarkably dependent on structure. The most active PCB congeners, 3,4,4',5-tetra-, 3,3',4,4'-tetra-, 3,3',4,4',5-penta- and 3,3',4,4',5,5'-hexachlorobiphenyl, are substituted at both para and at two or more meta positions. The four coplanar PCBs resembled 3-methylcholanthrene (3-MC) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) in their mode of induction of the hepatic drug-metabolizing enzymes. These compounds induced rat hepatic microsomal benzo(a)pyrene hydroxylase (aryl hydrocarbon hydroxylase, AHH) and cytochromes P-450a, P-450c and P-450d. 3,4,4',5-Tetrachlorobiphenyl, the least active coplanar PCB, also induced dimethylaminoantipyrine N-demethylase and cytochromes P-450b+e and resembled Aroclor 1254 as an inducer of the mixed-function oxidase system. Like Aroclor 1254, all the mono-ortho- and at least eight di-ortho-chloro analogs of the coplanar PCBs exhibited a "mixed-type" induction pattern and induced microsomal AHH, dimethylaminoantipyrine NM-demethylase and cytochromes P-450a-P-450e. Quantitative structure-activity relationships (QSARs) within this series of PCBs were determined by comparing their AHH induction potencies (EC50) in rat hepatoma H-4-II-E cells and their binding affinities (ED50) for the 2,3,7,8-TCDD cytosolic receptor protein. The results showed that there was an excellent correlation between AHH induction potencies and receptor binding avidities of these compounds and the order of activity was coplanar PCBs (3,3',4,4' -tetra-, 3,3',4,4',5-penta- and 3,3',4,4',5,5'-hexachlorobiphenyls) greater than 3,4,4',5-tetrachlorobiphenyl approximately mono-ortho coplanar PCBs greater than di-ortho coplanar PCBs. It was also apparent that the relative toxicities of this group of PCBs paralleled their biological potencies. The coplanar and mono-ortho coplanar PCBs also exhibit differential effects in the inbred C57BL/6J and DBA/2J mice. These compounds induce AHH and cause thymic atrophy in the former "responsive" mice whereas at comparable or higher doses none of these effects are observed in the nonresponsive DBD/2J mice. Since the responsiveness of these two mice strains is due to the presence of the Ah receptor protein in the C57BL/6J mice and its relatively low concentration in the DBA/2J mice, the results for the PCB cogeners support the proposed receptor-mediated mechanism of action.

Animals↗
PubMed1985

Effects of structure on binding to the 2,3,7,8-TCDD receptor protein and AHH induction--halogenated biphenyls.

The quantitative structure-activity relationships (QSARs) for polychlorinated biphenyl (PCB) congeners have been determined by comparing the EC50 values for three in vitro test systems, namely, aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) induction in rat hepatoma H-4-II-E cells and competitive binding avidities to the rat cytosolic receptor protein (using 2,3,7,8-tetrachlorodibenzo-p-dioxin as a radioligand). For several PCB congeners that are in vivo inducers of rat hepatic microsomal AHH, there was a linear correlation between the -log EC50 values for receptor and the -log EC50 values for AHH (or EROD) induction; moreover, a comparable linear relationship was observed between the -log EC50 values for AHH and EROD induction. Previous in vivo studies have shown that the most active PCB congeners 3,3',4,4'-tetra-, 3,4,4',5-tetra-, 3,3',4,4',5-penta-, and 3,3',4,4',5,5'-hexachlorobiphenyl, cause many of the biologic and toxic effects reported for the highly toxic halogenated aryl hydrocarbon, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Moreover, the monoortho-substituted homologs of the four coplanar PCBs also elicit comparable in vivo biologic and toxic responses. It was evident from the QSARs for PCBs that there was an excellent correspondence between the in vivo and in vitro potencies of the individual PCB congeners. The effects of substituents on both receptor binding and AHH/EROD induction was determined for a series of 4'-substituted (X)-2,3,4,5-tetrachlorobiphenyls (where X = H, Cl, Br, I, OH, OCH3, NO2, COCH3, F, CF3, CH3, C2H5, i-C3H7, n-C4H9 and t-C4H9). Not unexpectedly, there was a linear relationship between the -log EC50 values for AHH and EROD induction, and these results confirm that both enzymatic oxidations are catalyzed by the same cytochrome P-450 isozyme(s). The effects of substituent structure on receptor binding for 12 substituents was subjected to multiple regression analysis which correlates the relative binding affinities of the compounds with the physical chemical characteristics of the substituents. The analysis gave the following equation: log (1/EC50) = 1.53 sigma + 1.47 pi + 1.09 HB + 4.08 for n = 12, s = 0.18, r = 0.978; where n is the number of substituents, s is the standard deviation, r is the correlation coefficient, and sigma = electronegativity, pi = hydrophobicity (log P) and HB = hydrogen bonding capacity for the substituent groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1985

Effects of substituents on the cytosolic receptor-binding avidities and aryl hydrocarbon hydroxylase induction potencies of 7-substituted 2,3-dichlorodibenzo-p-dioxins. A quantitative structure-activity relationship analysis.

The binding affinities of 16 7-substituted 2,3-dichlorodibenzo-p-dioxins for the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) cytosolic receptor protein from male Wistar rats have been determined. The EC50 value for each compound was estimated by competitive displacement of [3H]TCDD and the data illustrated that the differences between competitive ligands were dependent on the substituent (X) group. The EC50 value for 7-trifluoromethyl-2,3-dichlorodibenzo-p-dioxin was 1.95 X 10(-8) M and was greater than 1000-fold more active than 7-amino-2,3-dichlorodibenzo-p-dioxin (EC50 = 2.88 X 10(-5) M). Multiple parameter linear regression analysis of the data for 14 different compounds gave the following equation: log (1/EC50) = 1.24 pi + 6.11. This demonstrated that the binding affinity was linearly dependent on the lipophilicity (pi) of the 7-X-group. This contrasted with a comparable analysis of the substituent effects on the binding of 13 4'-substituted 2,3,4,5-tetrachlorobiphenyls to the cytosolic receptor which showed that the lipophilicity, electronegativity, and hydrogen-bonding capacity were important physicochemical determinants which facilitated binding to the receptor protein. These data suggest that the halogenated dibenzo-p-dioxins and biphenyls may interact with different binding sites on the receptor or they may bind to the same site but exert different conformational effects on the receptor protein. For the 7-X-2,3,-dichlorodibenzo-p-dioxins, there was not a rank order correlation between receptor-binding EC50 values and the induction of aryl hydrocarbon hydroxylase (AHH) or ethoxyresorufin O-deethylase in rat hepatoma H-4-II E cells in culture. However, the data could be correlated with an estimate of substituent width, the STERIMOL factor (B5), i.e., log (AHH) = 1.29 log (binding) + 2.19 delta B5 - 1.31 (delta B5)2 - 1.48. The importance of a steric factor in the correlation between receptor binding and AHH induction for substituted dibenzo-p-dioxins and halogenated biphenyls is consistent with a structure-dependent conformational change(s) in the receptor protein:ligand complex after the initial binding event. Presumably, this latter process is associated with the steps involving interactions between the ligand:receptor complex and nuclear binding sites.

Animals↗
PubMed1984

Polychlorinated dibenzofurans (PCDFs): effects of structure on binding to the 2,3,7,8-TCDD cytosolic receptor protein, AHH induction and toxicity.

The effects of structure on the activity of 26 polychlorinated dibenzofurans (PCDFs) as competitive ligands for the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) rat hepatic cytosolic receptor protein were determined in a dose-response fashion. The ED50 values for these compounds varied 100 000-fold and the most active PCDFs were substituted in the 2,3,7 and 8 lateral positions; the ED50 for the most active PCDF, 2,3,4,7,8-pentachlorodibenzofuran was 1.5 X 10(-8) M which was only slightly less active than 2,3,7,8-TCDD (1.0 X 10(-8) M). A comparison of the binding affinities of several isomer pairs also indicated the relative importance of chlorine substitution at C-4 (or C-6) compared to C-1 (or C-9). Moreover, for some isomers it is apparent that C-4 (or C-6) substituents are more active than lateral substituents for facilitating ligand binding to the receptor protein. This is illustrated by the relative binding potencies of the following isomer pairs: 1,2,4,6,7-/1,2,4,7,8 = 19.2; 2,6,7-/2,3,8- = 2.2; 1,3,6-/1,3,8- = 19. Most of the PCDF structure-activity effects noted above were also observed for the induction of aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) in rat hepatoma H-4-II-E cells in culture. The most active compounds were also substituted in the lateral 2,3,7 and 8 positions and a comparison of C-4 (or C-6) vs. C-1 (or C-9) substituted PCDFs confirmed the higher induction potencies for most of the former group of compounds. The in vitro quantitative structure-activity data were complemented by in vivo studies which determined the relative activities of selected PCDFs as inducers of hepatic microsomal cytochrome P-448 dependent monooxygenases and their effects on body weight gain and thymus weights in immature male Wistar rats. The results indicated that for 2 series of isomers, namely the 2,3,4,7,8-, 1,2,4,7,8- and 1,2,4,7,9-pentachlorodibenzofurans and the 2,3,7,8-, 2,3,4,8- and 1,2,4,8-tetrachlorodibenzofurans, their biologic and toxic potencies were dependent on one major structural factor, the number of lateral chloro substituents. These results support the proposed role of the cytosolic receptor protein in mediating the biologic and toxic effects of the PCDFs.

Animals↗
PubMed1984

Polychlorinated biphenyls (PCBs) and polybrominated biphenyls (PBBs): biochemistry, toxicology, and mechanism of action.

Polychlorinated and polybrominated biphenyls are industrial chemical mixtures which have been implicated in numerous human poisonings in Taiwan and Japan (PCBs) and Michigan (PBBs). Moreover, these polyhalogenated biphenyls have been widely detected in the environment including the air, water, fish, wildlife, human adipose tissue, and blood and breast milk. A major problem associated with the analysis and toxicology of this group of chemicals is their chemical complexity (e.g., there are 209 possible PCB isomers and congeners) and the remarkable effects of structure on activity. This article will discuss the effects of structure on the biologic and toxic effects of individual PCB and PBB congeners as well as reconstituted mixtures. The results clearly show that like "dioxin" (or 2,3,7,8-TCDD), the PCBs and PBBs elicit their effects through a cytosolic receptor protein which preferentially binds with the toxins which are approximate isostereomers of 2,3,7,8-TCDD. The evidence for this mechanism of action will be discussed in detail.

Acne Vulgaris↗
PubMed1983

Competitive binding to the cytosolic 2,3,7,8-tetrachlorodibenzo-p-dioxin receptor. Effects of structure on the affinities of substituted halogenated biphenyls--a QSAR analysis.

The proposed mechanism of action of the toxic halogenated aromatics, typified by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), involves the initial binding to a high-affinity, low-capacity, cytosolic receptor protein. Previous studies have shown that several 4'-halo-2,3,4,5-tetrachlorobiphenyls bind to the TCDD receptor and that a lateral substituent on both phenyl rings is required for activity. Using an extended series of eighteen 4'-substituted-2,3,4,5-tetrachlorobiphenyls as probes, the effects of a variable lateral substituent on receptor binding affinity and the induction of aryl hydrocarbon hydroxylase (AHH) in vivo and in rat hepatoma H-4-II E cells have been determined. For most substituents, there was an excellent correlation between the rank-order potency for receptor binding and the rank-order potency for AHH induction. Based on in vitro binding affinities (EC50 values) of the 4'-substituted tetrachlorobiphenyls, a multiparameter regression equation was formulated correlating the binding constants to physicochemical substituent parameters. For thirteen compounds out of the present series, multiple regression analysis of the binding data led to the following equation: log(1/EC50) = 1.53 sigma + 1.47 pi + 1.09HB + 4.08, r = 0.978. The results suggest that halogen substitution on both phenyl rings is not a requirement for binding and that hydrophobic (pi) and electronic (sigma) substituent constants and a variable for hydrogen bond (HB) formation are significant parameters describing relative binding avidities of this series of substituted biphenyls for the TCDD receptor.

Animals↗
PubMed1983

Polychlorinated biphenyls as phenobarbitone-type inducers of microsomal enzymes. Structure-activity relationships for a series of 2,4-dichloro-substituted congeners.

Several polychlorinated biphenyl (PCB) isomers and congeners resemble phenobarbitone (PB) in their mode of induction of the hepatic drug-metabolizing enzymes; however, unlike PCBs which induce aryl hydrocarbon hydroxylase, no apparent structure-activity correlations have been reported. This study examines the effects of structure on the activity of a series of 2,4-dichloro-substituted biphenyls as inducers of several microsomal enzyme activities including dimethylaminoantipyrine N-demethylase, benzo[a]pyrene hydroxylase, aldrin epoxidase, and ethoxyresorufin O-deethylase. The results clearly illustrate a marked effect of structure on activity: all of the 2,4-dichloro-substituted PCBs resembled PB in their mode of induction. However, the potency of the induction response was dependent on the substitution pattern of the second phenyl ring (i.e. 2,3,4,5-tetrachloro greater than or equal to 2,3,4,5,6-pentachloro greater than 2,3,4,6-tetrachloro greater than 2,3,5,6-tetrachloro greater than 2,4,6-trichloro); the structure of the lower chlorinated ring also determined induction potency since the 2,4-dichloro-substituted PCBs were generally more active than their 4-chloro-substituted analogs, whereas the 2-substituted PCB homologs were inactive. The structural factors which typify the most active PB-type inducer, 2,2',3,4,4',5-hexachlorobiphenyl, include the presence of two para-, at least two meta- and two ortho-chloro substituents. In addition to the structure-activity correlations noted for PCBs, the 2,2',3,4,4',5-hexachlorobiphenyl congener also elicited a dose-response induction of two PB-inducible enzymes, aldrin epoxidase and dimethylaminoantipyrine N-demethylase.

Animals↗
PubMed1983

The comparative biologic and toxic potencies of polychlorinated biphenyls and polybrominated biphenyls.

Aroclor 1254 and fireMaster BP-6, two commercial polychlorinated biphenyl (PCB) and polybrominated biphenyl (PBB) preparations, exhibit comparable biologic and toxic effects. In the present study the commercial PBB was more active than Aroclor 1254 in causing thymic atrophy in male Wistar rats. However, a direct comparison of the relative effects of bromine vs chlorine substituents is not possible with the commercial PBB and PCB mixtures due to their complex congeneric composition. This study reports the synthesis and biologic and toxic effects of a series of laterally substituted 3,3',4,4'-tetrahalobiphenyls which contain the following variable molecular Cl/Br ratios; Br4, Br3Cl, Br2Cl2 (two isomers), BrCl3, and Cl4. 3,3',4,4'-Tetrabromobiphenyl and 3,4,4'-tribromo-3'-chlorobiphenyl (150 mumol/kg)-pretreated animals significantly inhibited the growth rate of and caused thymic atrophy in immature male Wistar rats whereas those isostereomers with reduced Br (and increased Cl) content were either less active or inactive. Pretreatment of male Wistar rats with 10 mumol/kg of the 3,3',4,4'-tetrahalobiphenyls and determination of their effects as inducers of the hepatic microsomal drug-metabolizing enzymes also illustrated the effects of the relative Cl/Br ratios on induction potencies. Both 3,3',4,4'-tetrabromo- and 3,4,4'-tribromo-3'-chlorobiphenyl maximally induced the cytochrome P-448-dependent monooxygenases, benzo[a]pyrene and 4-chlorobiphenyl hydroxylase; the order of potency of the other isostereomers was 4,4'-dibromo-3,3'-dichloro- congruent to 3,4-dibromo-3',4'-dichlorobiphenyl greater than 4-bromo-3,3',4'-trichloro- greater than 3,3',4,4'-tetrachlorobiphenyl. With few exceptions this order of potency was observed for the induction of benzo[a]pyrene hydroxylase and ethoxyresorufin O-deethylase in rat hepatoma cells in culture and for their relative binding affinities to the rat cytosolic receptor protein. The data clearly demonstrate that the biologic activities of this group of isosteric halogenated biphenyls are enhanced with increasing bromine substitution and also support the hypothesis that the activities of this class of chemicals are mediated through the receptor.

Animals↗
PubMed1983

Cellular and genetic basis for suppression of cytotoxic T cell generation by haloaromatic hydrocarbons.

Generation of allospecific cytotoxic T cells in C57Bl/6 mice is significantly impaired following exposure to TCDD at doses as low as 4 ng/kg. T helper activity, as assessed by the ability to produce Interleukin 2, and frequency of CTL precursors appear unaffected in treated animals and thus the TCDD-induced suppressor cells we have described are primarily responsible for the reduction in the CTL response. Suppression of CTL generation in DBA/2 mice requires a 10--100-fold greater dose than in C57Bl/6, consistent with the observation that the Ah locus gene(s) of DBA/2 mice code for TCDD receptors with low binding affinity for TCDD. Other haloaromatic hydrocarbons (3,3'4,4'-tetrachlorobiphenyl and Aroclor 1254), capable of binding to the TCDD receptor, also suppress CTL generation, whereas the 2,2',4,4',6,6'-hexachlorobiphenyl molecule that lacks affinity for the TCDD receptor does not suppress CTL. The immunotoxic effects of TCDD in C57B/6 and DBA/2 mice occur at dose levels below those required to induce mixed-function oxidase enzymes in the liver. Suppression of CTL by TCDD is associated with increased susceptibility to lethal herpes virus type II infection. These data suggest that low levels of TCDD may interact with cytoplasmic receptors for TCDD in the thymus and induce biologically significant immunosuppression through activation of suppressor cells.

Animals↗
PubMed1983

The effects of twenty-two organochlorine pesticides as inducers of the hepatic drug-metabolizing enzymes.

The effects of 22 organohalogen pesticides as inducers of hepatic drug-metabolizing enzymes in the immature male Wistar rat have been determined, this group includes four isomeric hexachlorocyclohexanes, technical chlordane, alpha-chlordane, gamma-chlordane, oxychlordane, trans-nonachlor, heptachlor, heptachlor epoxide, aldrin, dieldrin, kepone, toxaphene, mirex, hexachlorobenzene (HCB) and several DDT analogs. With the exception of HCB, all of the pesticides induced microsomal dimethylaminoantipyrine, N-demethylase and aldrin epoxidase activities and the cytochrome P-450 content of microsomes from animals pretreated with most of the compounds was also increased compared to control rats. These pesticides all resembled phenobarbitone in their mode of induction. The effects of HCB as a microsomal enzyme inducer resembled those observed after coadministration of phenobarbitone plus 3-methylcholanthrene.

Animals↗
PubMed1983

Polychlorinated benzene and phenol congeners as inducers of rat hepatic drug-metabolizing enzymes in immature male Wistar rats.

The effects of the higher chlorinated benzene and phenol congeners as inducers of the hepatic microsomal drug-metabolizing enzymes have been determined in the immature male Wistar rat by comparing the enzymic, electrophoretic, and spectral properties of the microsomes. 3,4,5-Trichlorophenol, 1,2,4,5-tetrachlorobenzene, 1,2,3,5-tetrachlorobenzene, 1,2,4-trichlorobenzene, and pentachlorobenzene induced 4-dimethylaminoantipyrine (DMAP) N-demethylase, an enzyme induced by phenobarbitone (PB) and several PB-type inducers. Hexachlorobenzene induced DMAP N-demethylase and aldrin epoxidase, two PB-inducible enzymes, and benzo[a]pyrene hydroxylase and ethoxyresorufin O-deethylase, two enzymes induced by 3-methylcholanthrene (MC). This mixed-type induction pattern has been previously reported for hexachlorobenzene. The remaining higher chlorinated benzene and phenol congeners were inactive as inducers of the drug-metabolizing enzymes in the immature male Wistar rats.

Animals↗
PubMed1982

Binding of metyrapone to dithionite-reduced cytochrome P-450 from rats treated with xenobiotics.

The in vitro binding of metyrapone to dithionite-reduced cytochrome P-450 in hepatic microsomes from rats treated in vivo with thirteen different xenobiotics was studied spectrophotometrically. The proportion of cytochrome P-450 that bound metyrapone increased 1.8-fold to about 78% following treatment with phenobarbitone (PB) and PB-type inducers (trans-stilbene oxide, 2,2',4,4'-tetrachloro-, 2,2',4,5,5'-pentabromo- and 2,2',4,4',5,5'-hexachlorobiphenyl) but remained unaltered following treatment with 3-methylcholanthrene (MC) and MC-type induces (benzo[a]pyrene, beta-naphthoflavone and 3,3',4,4'-tetrabromobiphenyl). The simultaneous induction of the PB-inducible and MC-inducible forms of cytochrome P-450 by administering Aroclor 1254 or by coadministering PB with MC increased the proportion of cytochrome P-450 that bound metyrapone to 74 and 78% respectively. PB treatment increased whereas MC treatment decrease the binding affinity for metyrapone by approximately 20-fold. Treatment with isosafrole or metyrapone itself failed to stimulate metyrapone binding. In contrast, pregnenolone-16 alpha-carbonitrile was indistinguishable from PB in its ability to increase the binding capacity and binding affinity for metyrapone. Our results indicate that metyrapone binding is not specific for cytochrome P-450b, the major PB-inducible hemoprotein, as has been proposed [V. Luu-The, J. Cumps and P. Dumont, Biochem. biophys. Res. Commun. 93, 776 (1980)].

Animals↗
PubMed1982

Halogenated biphenyls as AHH inducers: effects of different halogen substituents.

4'-Iodo-, 4'-bromo-, 4'-chloro- and 4'-fluoro-2,3,4,5-tetrachlorobiphenyl were administered to immature male Wistar rats and the effects of this homologous series of 4'-halo-2,3,4,5-tetrachlorobiphenyls on the microsomal drug-metabolizing enzymes were determined. All the halogenated biphenyls increased microsomal benzo[a]pyrene hydroxylase (or aryl hydrocarbon hydroxylase, AHH), ethoxyresorufin (ER) O-deethylase and dimethylaminoantipyrine (DMAP) N-demethylase. The effects of the 4'-halo-2,3,4,5-tetrachlorobiphenyls on the microsomal enzyme activities and on the relative peak intensities and spectral shifts of the reduced cytochrome P-450:CO and ethylisocyanide (EIC) binding difference spectra were similar to those observed after coadministration of phenobarbitone (PB) and 3-methylcholanthrene (MC). The relative activities of the halogenated biphenyls were determined using two in vitro assays; namely cytochrome P-448 associated induction in rat hepatoma H-4-II E cells in culture and competitive binding to the hepatic cytosolic Ah receptor protein from male Wistar rats. Dose-response experiments for the iodo, bromo, chloro and fluoro analogs gave EC50(M) values of 8.5 x 10(-9), 6.6 x 10(-8), 5.7 x 10(-7), and 3.3 x 10(-5), and 1.5 x 10(-6), 2.5 x 10(-6), 4.1 x 10(-6) and 2.5 x 10(-5) for the Er O-deethylase induction and receptor binding assays respectively. The relative potencies of the 4'-halo-2,3,4,5-tetrachlorobiphenyls followed the order I greater than Br greater than Cl greater than F for both assays and differences in the EC50 values for the iodo and fluoro analogs were greater than three orders of magnitude for ER O-deethylase induction in rat hepatoma cells in culture. One possible explanation for these effects may be associated with differences in the polarizability of the laterally substituted halogen groups. However, other differences in the physico-chemical properties of the halogen atoms may also be important.

Animals↗
PubMed1982

Cytochrome P-450-mediated metabolism of biphenyl and the 4-halobiphenyls.

The in vitro metabolism of biphenyl, 4-fluoro-, 4-chloro-, 4-bromo- and 4-iodobiphenyl by cytochrome P-450-dependent monooxygenases was investigated using hepatic microsomes from immature male rats pretreated with phenobarbitone or 3-methylcholanthrene. The major route of metabolism of biphenyl and the 4-halobiphenyls was 4'-hydroxylation, i.e. para to the phenyl-phenyl bridge. The minor route of metabolism apparently changed from 2-hydroxylation for biphenyl (i.e. ortho to the phenyl-phenyl bridge) to 3-hydroxylation for all 4-halobiphenyls (i.e. ortho to the halogen). In marked contrast to biphenyl, the regioselectivity of 4-halobiphenyl metabolism was not altered by pretreatment of rats with either phenobarbitone or 3-methylcholanthrene. The overall rate of metabolism of 4-fluoro- and 4-bromobiphenyl to water-soluble metabolites increased 2-fold and 5- to 6-fold using microsomes from rats pretreated with phenobarbitone and 3-methylcholanthrene respectively. In contrast, the overall rates of metabolism of 4-chloro- and 4-iodobiphenyl were refractory to the inductive effects of phenobarbitone but were increased more than 10-fold following pretreatment with 3-methylcholanthrene. There was a correlation between the apparent binding affinities of microsomes from phenobarbitone-treated rats for biphenyl and the 4-halobiphenyls and their calculated log octanol/water partition coefficients (lipophilicity). However, the effects of the halogen substituents on the rates of metabolism of the 4-halobiphenyls by microsomes from control and induced rats did not correlate with their binding affinities or with any physiochemical differences between the fluoro, chloro, bromo and iodo substituents.

Animals↗
PubMed1982

Binding of polychlorinated biphenyls classified as either phenobarbitone-, 3-methylcholanthrene- or mixed-type inducers to cytosolic Ah receptor.

It has been postulated that reversible, high-affinity binding of 3-methylcholanthrene(MC)-type inducers to a receptor protein (the Ah receptor) in hepatic cytosol is essential for induction of aryl hydrocarbon hydroxylase (AHH) enzymic activity. To test this postulate, the binding affinities of 16 highly-purified, synthetic chlorinated biphenyl (PCB) congeners, which have been categorized either as phenobarbitone(PB)-, MC- or mixed (PB + MC)-type inducers of cytochrome P-450-dependent monooxygenase have been examined. The affinity of individual biphenyl congeners for the receptor was determined by their competition with 2,3,7,8-[3H]tetrachlorodibenzo-p-dioxin ([3H]TCDD) for specific cytosolic binding sites as measured by sucrose density gradient analysis following dextran-charcoal treatment. This assay demonstrates (a) that the receptor binds with highest affinity to 3,3', 4,4',5-pentachlorobiphenyl and 3,3',4,4'-tetrachlorobiphenyl ('pure MC-like' inducers); (b) mixed-type PCB inducers also bind to the receptor but with an affinity (average EC50-value of 8.6 microM) lower than that for 3,3',4,4',5-pentachlorobiphenyl; this corresponds with their relatively lower potencies as AHH inducers; (c) the receptor binds 2,2',4,4'-tetra-, 2,3,4,5-tetra-, 2,2',4,4',5,5'-hexa- and 2,3',4,4',5',6-hexachlorobiphenyl at high concentrations (0.1 mM), whereas PB fails to bind, even at a concentration of 10 mM. All PCBs tested competed with [3H]TCDD for Ah receptor, but there was a great variation in their relative binding affinities. The fact that two chlorinated biphenyls classed as 'PB-like' inducers and two chlorinated biphenyls which are neither 'PB- nor MC-type' inducers competed, coupled with the fact that PB did not bind to the receptor suggest that chemicals other than "pure MC-type' inducers can bind to the cytosolic receptor. Affinity of the binding dictates the relative potency of given PCB congeners as inducers of cytochrome P-448.

Animals↗
PubMed1982

Polybrominated biphenyls as aryl hydrocarbon hydroxylase inducers: structure-activity correlations.

The synthesis of all possible laterally-substituted polybrominated biphenyl (PBB) congeners containing two para bromines is described. Using enzymic, electrophoretic and ligand-binding assays that distinguish between phenobarbitone(PB)- and 3-methylcholanthrene(MC)-type inducers, the synthetic PBBs were evaluated as inducers of liver microsomal drug-metabolizing enzymes in the immature male Wistar rat. 4,4'-Dibromobiphenyl resembled PB in its mode of induction whereas all the meta-brominated derivatives of 4,4'-dibromobiphenyl, namely 3,4,4'-tri, 3,4,4',5-tetra-, 3,3', 4,4'-tetra-, 3,3',4,4',5-penta- and 3,3',4,4',5,5'-hexabromobiphenyl, resembled MC in their mode of induction. The results obtained with 3,4,4'-tribromobiphenyl demonstrate that, in contrast to the polychlorinated biphenyls (PCBs), a single meta halogen substituent is sufficient to abolish the PB-type characteristics of 4,4'-dibromobiphenyl and convert it to a strictly MC-type inducer. PBBs which induce AHH activity must be substituted at both para positions and at one, two, three or four meta positions. Ortho-substitution of PBBs which contain only lateral bromine groups may also give compounds which are aryl hydrocarbon hydroxylase (AHH) inducers. One of the MC-type PBBs, namely 3,3',4,4'-tetrabromobiphenyl, which has been tentatively identified in the commercial PBB mixture, fireMaster BP-6, was at least 50 times more potent as an inducer of AHH activity than the commercial PBB mixture. The induction of AHH by 3,3',4,4'-tetrabromobiphenyl was accompanied by a dose-dependent decrease in both thymus and spleen weights. The thymus and/or spleen weights were decreased in rats treated with the other MC-type PBBs which further supports the correlation between the toxicity of the PBBs and their ability to induce AHH.

Animals↗
PubMed1982

PCB isomers and congeners: induction of aryl hydrocarbon hydroxylase and ethoxyresorufin O-deethylase enzyme activities in rat hepatoma cells.

The effects of structure on the activity of 15 polychlorinated biphenyl (PCB) isomers and congeners as inducers of cytochrome P-448-dependent monooxygenases in rat hepatoma cell cultures was investigated. All the PCBs which have previously been classified as aryl hydrocarbon hydroxylase (AHH) inducers in the immature male Wistar rat also induced benzo[a]pyrene hydroxylase and ethoxyresorufin (ER) O-deethylase activity in the rat hepatoma H-4-II-E cells. The relative activities of the compounds were evaluated by comparing the doses required to half-maximally induce the two enzyme activities. The most potent PCB inducer, 3,3',4,4',5-pentachlorobiphenyl, exhibited molar EC50 values of 2.48 X 10(-10) and 2.40 X 10(-10) for the induction of ER O-deethylase and benzo[a]pyrene hydroxylase enzyme activities, respectively. These values were only 3- to 4-fold lower than the data obtained for the highly toxic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The relative activities of the PCB congeners as inducers of cytochrome P-448-dependent monooxygenase in vitro were similar to their potencies as microsomal enzyme inducers in the immature male rat.

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