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Biomedical subjects

S Safe

Publications and source records attributed to S Safe.

At least 271 records · Page 15Linked to original sources
PubMed1980

Polychlorinated biphenyl isomers and congeners as inducers of both 3-methylcholanthrene- and phenobarbitone-type microsomal enzyme activity.

Highly purified synthetic polychlorinated biphenyls substituted in the meta and para positions of both phenyl rings and at one ortho position were administered to male Wistar rats and the effects of these compounds on the microsomal drug-metabolising enzymes were evaluated. The in vivo effects of these compounds were determined by measuring the microsomal benzo[a]pyrene hydroxylase, dimethylaminoantipyrine 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 binding difference spectra. The results were compared to the effects of administering phenobarbitone (PB), 3-methylcholanthrene (MC), 2,2',4,4'-tetrachlorobiphenyl (TCBP-II) (a PB-type inducer), 3,3',4,4'-tetrachlorobiphenyl (TCBP-I) (an MC-type inducer), PB plus MC (coadministered) and TCBP-II + TCBP-I (coadministered) to the test animals. At dosage levels of 30 and 150 mumol . kg-1, pretreatment with 2,3,3',4,4'-pentachlorobiphenyl (PCBP-II), 2,3',4,4',5-pentachlorobiphenyl (PCBP-I), 2,3,3',4,4',5-hexachlorobiphenyl (HCBP-II) and 2,3,3',4,4',5-hexachlorobiphenyl (HCBP-III) gave hepatic microsomes with enzymic and spectral properties consistent with a mixed pattern of induction. These polychlorinated biphenyl (PCB) isomers and congeners have been identified as either major or minor components of the commercial PCB mixtures and must contribute to their activity as MC-type inducers. The only PCB isomer in this series which was not a mixed type inducer was 2,3',4,4',5,5'-hexachlorobiphenyl (HCBP-I) which appeared to be a PB-type inducer. This contrasted to the mixed-type activity observed for 2,3',4,4',5,5'-hexabromobiphenyl which was isolated from a commercial polybrominated biphenyl (PBB) mixture.

Animals↗
PubMed1980

The effects of ortho chloro substituents on the retention of PCB isomers in rat, rabbit, Japanese quail, guinea pig and trout.

A mixture of 2,2',4,4',6,6'-,2,2',4,4',5',6-,2,2',4,4',5,5'-,2',3,4,4',5,5'- and 3,3',4,4',5,5'-hexachlorobiphenyls (HCBP) was administered by gastric lavage to rats, guinea pigs, rabbits, Japanese quail and trout, and the concentrations in the fat or whole carcass were determined after 29 days. The total HCBP levels in rat, rabbit and guinea pig fatty tissue were 8.27, 6.84 and 4.74 ppm, respectively: whereas 3.02 and 2.15 ppm of the HCBPs were detected in the trout and Japanese quail carcasses. The extent of ortho chloro substitution markedly affected the levels of the individual HCBP isomers retained in the test animals; the rabbit and guinea pig preferentially retained the HCBPs with 0,1 and 2 ortho chloro substituents, the Japanese quail retained only the 3,3',4,4',5,5'-HCBP isomer, whereas no striking preferences in HCBP isomer retention in the rat and trout were observed. The marked differences in the retention of HCBP isomers with 0, 1, 2, 3 and 4 ortho chloro substitution by different animal species should be considered in chronic toxicity studies since the most toxic polychlorinated biphenyls have minimal (1 or 0) ortho chloro substituents.

Adipose Tissue↗
PubMed1980

The in vitro metabolism of 2,2',4,4',5,5'-hexabromobiphenyl.

Radiolabelled 2,2',4,4',5,5'-hexabromobiphenyl was metabolized in vitro by rat liver microsomal enzymes to give more polar ether soluble lipophilic metabolites, trichloroacetic acid soluble conjugates and a macromolecular adduct fraction. The rates of formation of the three metabolic fractions were significantly enhanced using Firemaster BP-6 and 2,2',4,4',5,5'-hexabromobiphenyl induced microsomal enzymes. Comparative metabolic studies with the 4-brombiphenyl substrate showed that the lower brominated biphenyl substrate was more readily metabolized and the rate of metabolism was enhanced only with the Firemaster BP-6 induced microsomal enzymes and not the 2,2', 4,4',5,5'-hexabromobiphenyl induced enzyme system.

Animals↗
PubMed1979

The detection of enzyme induction by rat liver microsomes prepared by isoelectric precipitation.

A comparison was made of various indices of the hepatic drug-metabolizing apparatus associated with the postmitochondrial superntant, microsomes harvested by differential centrifugation, and microsomes harvested by isoelectric precipitation from control, phenobarbitone-pretreated and 3-methylcholanthrene-pretreated rats. The metabolic capabilities and distinctions between control and induced rats for each of the three liver preparations compared favourably as determined by the concentration of cytochrome b5 and P-450 and by the activity of NADPH-cytochrome c reductase, 4-dimethylaminoantipyrine N-demethylase and aryl hydrocarbon (benzo[a]pyrene) hydroxylase. The results suggest that the relatively simple isoelectric precipitation technique is a useful alternative to the conventional method of differential centrifugation for the preparation of hepatic microsomes.

Animals↗
PubMed1979

Avian metabolism of halogenated biphenyls.

1. The metabolism of several halogenated biphenyls has been studied using poultry as a model system. The substrates 4-chlorobiphenyl and 4-bromobiphenyl each yielded two metabolites (4'-chloro-4-biphenylol, 4'-chloro-3,4-biphenyldiol; 4'-bromo-4-biphenylol, 4'-bromo-3,4-biphenyldiol), while 4,4'-dichlorobiphenyl yielded only one metabolite (4,4-dichloro-3-biphenylol). 2. Metabolites were not found in eggs collected for 7 days following the administration of the substrate.

Animals↗
PubMed1979

The metabolically mediated DNA damage and subsequent DNA repair by 4-chlorobiphenyl in Chinese hamster ovary cells.

The metabolism of [3H]-4-chlorobiphenyl (CB) by Chinese hamster ovary cell cultures resulted in the formation of lipophilic hydroxylated metabolites, trichloroacetic acid soluble conjugates and covalent macromolecular adducts. The major lipophilic metabolite was chromatographically similar to 4'-chloro-4-biphenylol. The intracellular macromolecules were fractionated into protein, RNA and DNA. Although protein was the major target of covalent interaction with [3H]-CB and contributes 85% of the macromolecular binding, the specific binding of [3H]-CB to DNA was 3.5 and 1.4 times higher than that observed for protein and RNA respectively. Incubation of the CHO cells with 10 mM CB, [3H]-thymidine and 10 mM hydroxyurea for 2.5 hr resulted in a 1.6 fold increase in unscheduled DNA synthesis. The data demonstrated that the readily metabolized CB congener not only reacts with mammalian cell macromolecules, including DNA, but the DNA damage can also be demonstrated by its subsequent repair.

Animals↗
PubMed1978

In vitro metabolism of 4-chlorobiphenyl by control and induced rat liver microsomes.

The in vitro metabolism, mechanism of metabolism, and macromolecular binding of a monochlorobiphenyl component of commercial polychlorinated biphenyls (PCB) have been investigated. 4-Chlorobiphenyl was metabolized by rat liver microsomes in the presence of NADPH to yield a major metabolite, 4'-chloro-4-biphenylol, and a number of minor metabolites. The metabolism of deuterium-labeled 4-chlorobiphenyl proceeded with the NIH shift of the isotope and no observed isotope effect thus indicating the intermediacy of an arene oxide. Noninduced rat liver microsomes mediated the covalent binding between the 4-chlorobiphenyl and 4'-chloro-4-biphenylol substrates and endogenous microsomal protein. Prior in vivo administration of a commericial PCB preparation, Aroclor 1248 (Monsanto Chemical Co., containing 48 percent by weight of chlorine), resulted in an induced microsomal preparation which significantly increased the substrate-protein binding. The effect of various inhibitors on protein binding was investigated. Aroclor 1248 induced microsomes mediated binding of 4-chlorobiphenyl to endogenous and exogenous nucleic acids, indicating a possible mechanism for the previously reported mutagenic action of this chlorobiphenyl. The spectral properties of Aroclor 1248 induced cytochrome P-450 were investigated and compared with the pentobarbital-induced cytochrome fraction.

Animals↗
PubMed1978

A comparison of the in vitro metabolism of biphenyl and 4-chlorobiphenyl by rat liver microsomes.

The comparative metabolism of the hydrocarbons, biphenyl and 4-chlorobiphenyl, was investigated using two different preparations of rat hepatic microsomes. The assay was designed to account for all the metabolic products which included the ether soluble lipophilic metabolites, low molecular weight conjugates, and macromolecular adducts, and to determine the effects of induction with Aroclor 1254 and 1248, two commercial polychlorinated biphenyl (PCB) preparations. 4-chlorobiphenyl was the more metabolically active substrate with the induced and control enzymes. In most metabolic fractions biphenyl was less inducible by the PCB's, with the exception of the 2-biphenylol metabolite which was induced ca. 18-fold. Preincubation of the microsomes with carcinogens did not enhance biphenyl 2-hydroxylation. Instead, a general inhibition of metabolic activity was observed for both biphenyl and 4-chlorobiphenyl substrates. Preincubation with phenobarbitone, a noncarcinogen, did not change the microsome-mediated metabolism of biphenyl or 4-chlorobiphenyl. The substitution of a single halogen atom on the biphenyl nucleus altered both the reactivity and pattern of metabolites for these substrates.

Animals↗
PubMed1978

FireMaster BP-6: fractionation, metabolic and enzyme induction studies.

FireMaster BP-6 is a commercial polybrominated biphenyl (PBB) preparation containing a complex mixture of isomers with the major component being identified as 2,2',4,4',5,5'-hexabromobiphenyl. Column chromatographic techniques have been developed in which the crude FireMaster is separated into three fractions, F1, F2, and F3, in increasing order of polarity. F1 consists of highly purified 2,2',4,4',5,5'-hexabromobiphenyl (94%) whereas F2-F3 contain less of this isomer and correspondingly more of the other bromobiphenyl components. Previously we have shown that crude FireMaster BP-6 is metabolized in mammals to give hydroxylated degradation products and the metabolism of F1, not unexpectedly, gives comparable results. It is well known that PBBs are effective inducers of diverse microsomal enzymes including including the aryl hydrocarbon hydroxylase (AHH) system. The effects of FireMaster BP-6 and F1-F3 as AHH inducers have been investigated by using the following approach: the substrates used to monitor AHH activity are model halogenated aromatic compounds; the levels of metabolites and metabolite conjugates formed have been quantitated for control and induced enzymes; the levels of macromolecular adducts have also been quantitated for the inducers. This approach thus not only measures the rate of increase of detoxification products (metabolites and metabolite conjugates) but also monitors the macromolecule adduct formation which represents a toxification route. The effects of the PBBs as AHH inducers will be discussed in terms of the above approach.

Animals↗
PubMed1977

Eburicol, lichesterol, ergosterol, and obtusifoliol from polyene antibiotic-resistant mutants of Candida albicans.

Two classes of polyene-resistant mutants were isolated from survivors of N-methyl-N'-nitro-N-nitrosoguanidine treatment of a wild-type Candida albicans. An analysis of the major sterols of one class revealed an accumulation of lichesterol and fecosterol while the other class accumulated eburicol, obtusifoliol, and lanosterol with minor quantities of C28 sterols.

Amphotericin B↗
PubMed1977

An assessment of the effects of enzyme inducers on aryl hydrocarbon hydroxylase activity.

The aryl hydrocarbon hydroxylase activity for control, Aroclor 1254 and FireMaster BP-6 induced hepatic microsomes was determined using 4-chlorobiphenyl, a model PCB isomer, as the substrate. The assay system was used to quantitate the amount of metabolites, conjugates and macromolecular adducts formed for the induced and control microsomes. The metabolites and conjugates were designated detoxification (D) products and the macromolecular adducts designated as toxification (T) products. From the data it was then possible to determine a T/D index for each inducer and it is proposed that this index is useful in assessing the potential toxicity of microsomal enzyme inducers.

Animals↗
PubMed1976

The ultraviolet absorption spectra of some chlorinated biphenyls.

The UV spectra of 29 chlorobiphenyls have been examined. With increasing chloro substitution in which there are less than two chlorine groups ortho to the Ph-Ph bond the lambdamax values for the K band (attributed to the conjugation between the two phenyl rings) are shifted to longer wavelengths and for the more highly substituted chlorobiphenyls there is also a bathochromic shift of the main band (due to the benzenoid skeleton). Introduction of two or more chlorine atoms ortho to the Ph-Ph bond results in a hipsochromic shift of K band and diminished xi value due to steric inhibition of resonance between the two phenyl rings. The sterically hindered chlorobiphenyls and the more highly chlorinated Aroclors also exhibit a series of low-intensity fine-structured absorption maxima between 268-302 nm. The UV spectra of chlor-biphenyls are particularly diagnostic with respect to the degree of substitution at the 2, 2', 6 and 6' positions and can be used in the structural analysis of separated chlorobiphenyls. The data may also aid in correlating the photochemical reactivities.

Chemical Phenomena↗
PubMed1976

The in vitro hydroxylation of 4'-chloro-4-biphenylol by a mushroom tyrosinase preparation.

Incubation of 4'-chloro-4-biphenylol with a mushroom tyrosinase preparation gave the catechol, 4'-chloro-3,4-biphenyldiol as the sole in vitro metabolite. This compound was identical with the major rat urinary metabolite of 4'-chloro-4-biphenylol and thus confirms the structure assigned to the metabolite. This result also demonstrates a possible degradation pathway of hydroxylated chlorobiphenyls which are themselves the major metabolic degradation products of polychlorinated biphenyls.

Catechol Oxidase↗