Search PubMed⌕ Search

Biomedical subjects

S Safe

Publications and source records attributed to S Safe.

At least 253 records · Page 14Linked to original sources
PubMed1982

Halogenated biphenyls: molecular toxicology.

The biologic and toxic effects of polychlorinated biphenyls (PCBs) are remarkably dependent on their structure. The most toxic PCBs, namely 3,3',4,4'-tetra-, 3,3',4,4',5-penta- and 3,3',4,4',5,5'-hexachlorobiphenyl are substituted in at least one meta and para position on both phenyl rings (i.e., the lateral positions) and contain no ortho-chloro substituents. These three congeners and a fourth PCB, namely 3,4,4',5-tetrachlorobiphenyl, are approximate isostereomers of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and, in common with TCDD, induce hepatic microsomal benzo[a]pyrene or aryl hydrocarbon hydroxylase (AHH) in rats and rat hepatoma cells in culture. The mono-ortho substituted analogs of the four laterally substituted PCBs also induce microsomal AHH activity and simultaneously enhance microsomal enzyme activities which are inducible by phenobarbitone (PB). This group of PCBs exhibits many of the properties of 2,3,7,8-TCDD and related polychlorinated dibenzo-p-dioxins; there is a close parallel in the relative potencies of these PCBs for AHH induction and their binding affinities for the Ah receptor protein and some of these PCBs are also toxic. Preliminary studies on other halogenated biphenyls confirm that the polarizability of a lateral substituent is an important factor in their activity as AHH inducers (i.e., I greater than Br greater than Cl greater than F). However, preliminary results with other substituted halogenated biphenyls suggest that additional structural factors are also important in determining the activity of these compounds.

Animals↗
PubMed1981

Polychlorinated biphenyls as inducers of hepatic microsomal enzymes: effects of di-ortho substitution.

All of the 13 possible polychlorinated biphenyl (PCB) isomers and congeners substituted at both para positions, at least two meta positions (but not necessarily on the same ring) and at two ortho positions have been synthesized and tested as rat hepatic microsomal enzyme inducers. The effects of these compounds were evaluated by measuring microsomal benzo-[a]pyrene (B[a]P) hydroxylase, 4-chlorobiphenyl (4-CBP) hydroxylase, 4-dimethylaminoantipyrine (DMAP) N-demethylase and NADPH-cytochrome c reductase activities, the cytochrome b5 content and the relative peak intensities and spectral shifts of the carbon monoxide(CO)- and ethylisocyanide(EIC)-difference spectra of ferrocytochrome P-450. The results were compared to the effects of administering phenobarbitone (PB), 3-methylcholanthrene (MC) and PB plus MC (coadministered). At dose levels of 150 mumol . kg-1, all of the PCB congeners, except 2,3',4,4',5',6-hexachlorobiphenyl, significantly enhanced hepatic microsomal cytochrome P-450 content, B[a] P hydroxylase and/or DMAP N-demethylase activities compared to the control (corn oil-treated) animals. Only 5 of these compounds, namely 2,3,4,4',5,6-hexa-, 2,2',3,3',4,4'-hexa-, 2,2',3',4,4',5-hexa-, 2,3,3',4,4',6-hexa-and 2,2',3,3',4,4',5-heptachlorobiphenyl, enhanced microsomal B[a]P hydroxylase, 4-CBP hydroxylase, NADPH-cytochrome c reductase and DMAP N-demethylase activities in a manner consistent with a mixed pattern of induction. The results suggest that PCB isomers and congeners substituted at both para positions, at least two meta positions, at two ortho positions and containing a 2,3-4-trichloro substitution pattern on one ring are mixed-type inducers; in addition the effects of 2,3,4,4',5,6-hexachlorobiphenyl were also consistent with a mixed pattern of induction.

Animals↗
PubMed1981

Potent induction of rat liver microsomal, drug-metabolizing enzymes by 2,3,3',4,4',5-hexabromobiphenyl, a component of fireMaster.

The multistep synthesis and purification of 2,3,3',4,4',5-hexabromobiphenyl (HBBp) is described. Capillary gas chromatography revealed that HBBp comprises 0.05% of the industrial polybrominated biphenyl (PBB) mixture, fireMaster BP-6 (lot 7062). When administered to immature male Wistar rats, HBBp caused a dose-dependent increase in (a) the activity of benzo[a]pyrene (B[a]P) hydroxylase (AHH) and 4-chlorobiphenyl (4-CBP) hydroxylase and (b) the concentration of cytochrome P-450. Sodium dodecyl sulfate (SDS)-gel electrophoresis indicated that these increases in cytochrome P-450 and cytochrome P-450-dependent monooxygenase activities were accompanied by a dose-dependent intensification of a protein of relative molecular weight (Mr) 55 000 which comigrated with the major 3-methylcholanthrene(MC)-inducible form of cytochrome P-450 (i.e., cytochrome P-448). Like MC, but in contrast to phenobarbitone (PB), HBBp competitively displaced 2,3,7,8-[3H]tetrachlorodibenzo-p-dioxin ([3H]-TCDD) from the cytosolic protein thought to be the receptor for cytochrome P-448 induction. The results indicate that HBBp is a potent inducer of cytochrome P-448 and as such is the third MC-type inducer identified in fireMaster BP-6.

Animals↗
PubMed1981

Aryl hydrocarbon hydroxylase (AHH) induction by polybrominated biphenyls (PBBs): enchancement by photolysis.

Irradiation of the commercial polybrominated biphenyl (PBB( mixture, fireMaster BP-6, in cyclohexane solution at 300 nm for 930 min resulted in a marked diminution of the major components of the mixture. Administration of the photolyzed PBB mixture of fireMaster BP-6 to immature male Wistar rats caused both dose-related decreases in thymus weight and increase in hepatic microsomal benzo[a]pyrene hydroxylase (AHH), 4-dimethylaminoantipyrine N-demethylase and NADPH-cytochrome c reductase activities and cytochrome P-450 content. The dose effecting half-maximal AHH induction for the photolyzed PBBs (9 mg . KG-1) was approximately 6 times lower than that of fireMaster BP-6 (50 mg. kg-1). Furthermore, the concentration of photolyzed PBBs (2 micrometers) required to displace 50% of the specifically-bound [3H] TCDD from its high-affinity cytosolic Ah receptor was approximately 150 times lower than that required for fireMaster BP-6 (300 micrometers), as measured by sucrose density gradient centrifugation analysis. The results suggest that the photolysis of the commercial PBB mixture yields products which possess increased biologic activity.

Animals↗
PubMed1981

Octachloronaphthalene induction of hepatic microsomal aryl hydrocarbon hydroxylase activity in the immature male rat.

Administration of octachloronaphthalene to immature male Wistar rats resulted in a dose-dependent increase in several enzymic, electrophoretic and spectral parameters associated with induction of the hepatic microsomal enzymes. Compared to corn-oil (control)treated animals octachloronaphthalene (150 mumol . kg-1) induced hepatic cytochrome P-450 (1.5-fold), benzo [alpha] pyrene hydroxylase (18-fold) and 4-chlorobiphenyl hydroxylase (18-fold) enzyme activities. In addition to increases in the relative peak intensities of the reduced microsomal cytochrome P-450 : CO and ethylisocyanide (EIC) difference spectra the peak maxima were observed at 448.5 and 452.2/428.0 nm, respectively. The effects of administering octachloronaphthalene to the rat were similar to those observed after pretreatment with 3-methylcholanthrene (MC) and electrophoresis of the induced microsomal proteins showed that both compounds enhance heme-staining peptides with comparable electrophoretic mobilities. Moreover coadministration of MC (3 x 100 mumol . kg-1) and octachloronaphthalene (2 x 150 mumol . kg-1) indicated that their inductive effects were not additive. It was concluded that octachloronaphthalene was an MC-type inducer of hepatic microsomal enzymes.

Age Factors↗
PubMed1981

Identification of a toxic impurity in commercial diphenylamine.

The impurity in commercial diphenylamine which induces polycystic kidney disease in rats has been identified as N,N,N'-triphenyl-p-phenylenediamine. The structure of the compound was confirmed by mass and proton magnetic resonance spectrometry and by comparison with a synthetic standard prepared by the Ullman coupling of iodobenzene and p-phenylenediamine or N,N-diphenyl-p-phenylenediamine. Laboratory studies with highly purified diphenylamine indicated that N,N,N'-triphenyl-p-phenylenediamine can be formed by heating diphenylamine.

Aniline Compounds↗
PubMed1981

Effects of Aroclor 1254-induced rat liver S-9 fraction on benzo[a]pyrene-mediated DNA damage and benzo[a]pyrene metabolism in cultured human skin fibroblasts.

Incubation of cultured normal human skin fibroblasts with benzo[a]pyrene (B[a]P) resulted in covalent binding of B[a]P to protein, RNA and DNA. B[a]P adduct formation was increased when the cultured cells were also treated with the 9,000 g hepatic microsomal supernatant (S-9) fraction from rats pretreated with Aroclor 1254, a commercial preparation of polychlorinated biphenyls (PCBs). Comparison with control experiments which included the incubation with corn oil-induced S-9 fraction indicated that the enhanced B[a]P-adduct formation in the host cells was related to the induction of hepatic NADPH-dependent microsomal monooxygenase activity by Aroclor 1254 in the S-9 fraction. Parallel experiments showed that this Aroclor-induced enzymic activity was responsible for B[a]P-mediated DNA damage as measured by unscheduled DNA synthesis (UDS) in the cells. Similarly, administration of rat hepatic S-9 induced by 3-methylcholanthrene (MC) and phenobarbitone (PB) caused B[a]P-mediated DNA damage in cultured human skin fibroblasts.

Animals↗
PubMed1980

Bromo and chlorobiphenyl metabolism: gas chromatography mass spectrometric identification of urinary metabolites and the effects of structure on their rates of excretion.

The identification of the hydroxylated rat urinary metabolites of the 2-, 3- and 4-chlorobiphenyls and 2-, 3- and 4-bromobiphenyls has been determined by gas chromatographic mass spectrometric analysis of their corresponding methyl ether derivatives. The electron impact fragmentation patterns of the bromotheoxybiphenyls and chloromethoxybiphenyls were used to assign the position of the methyoxyl group (ortho, meta or para to the biphenyl bond); the mass spectra of the corresponding [2H5]halobiphenyls confirmed the sites of the hydroxylation by distinguishing between the halophenyl and phenyl rings. The results illustrated that ring hydroxylation occurs predominantly at the para positions of the biphenyl nucleus and at sites which are ortho and para to the halogen substituents. 4,4'-Dimethoxyhalobiphenyls are major urinary metabolites of the 2- and 3-halobiphenyls and the rapid formation of these metabolites is illustrated in a time course study which monitors the urinary metabolites formed after the separate coadministration of the isomeric chlorobiphenyl and bromobiphenyl substrates to rats.

Animals↗
PubMed1980

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

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.

Animals↗