Metabolism Of Biphenyl Research Articles

The metabolism of biphenyl. III. Phenolic metabolites in the pig.

Abstract The phenolic metabolites of biphenyl in both male and female pigs were qualitatively and quantitatively analysed as trimethylsilyl (TMS) ethers by combined gas chromatography/mass spectrometry and gas chromatography, respectively. This xenobiotic was metabolized mainly to mono–hydroxylated biphenyl, and in small amounts to di– and tri–hydroxylated biphenyls. Urinary excretion was the only route of elimination of these compounds from the body. The total urinary recovery in male pigs was 44.8 % of the dose 96 hrs after administration of the drug, and the corresponding value in female pigs was 27.6%. The main part of the urinary metabolites was excreted during the first 24 hrs after dosing in both sexes.

The metabolism of biphenyl. I. Metabolic disposition of 14C-biphenyl in the rat.

Abstract The metabolic disposition of 14C–biphenyl in the rat was studied by liquid scintillation counting. The rats were given an oral dose of 14C–biphenyl (100 mg/kg, 0.7–1.0 μci) and the total excretion of radioactivity after 96 hrs was 92.2 % of the dose. Urinary excretion accounted for 84.8 % and faecal excretion for 7.3% of the dose. Most of this radioactivity, 75.8 % and 5.8% respectively, was excreted within 24 hrs. Only trace amounts of 14CO2 were detected in the expired air and 0.6% of the dose was found to be still present in the rats 96 hrs after biphenyl administration. Extraction and fractionation of the 24 hrs urine samples showed that the largest fraction (nearly 30% of the dose) consisted of conjugated phenolic metabolites. Acidic metabolites accounted for a quarter of the dose and the low levels of expired 14CO2 indicated that these were not products resulting from extensive degradation and decarboxylation.

The metabolism of biphenyl. II. Phenolic metabolites in the rat.

Abstract The metabolic conversion of biphenyl to phenolic metabolites was studied in the rat. The metabolites were identified by mass spectrometry and quantified by gas chromatography following conversion to their trimethylsilyl (TMS) ethers. The main route of excretion was via the urine, and the major part (22.3 %) of the biphenyl metabolites was excreted in the first 24 hrs. The total urinary recovery 96 hrs after administration was 29.5 % of the dose and the metabolites detected were conjugates of mono–, di– and tri–hydroxy derivatives of biphenyl as well as the meta– and para–methyl ethers of the catecholic compounds. The two main urinary metabolites were 4–hydroxybiphenyl (7.7 %) and 4,4′–dihydroxybiphenyl (11.4 %). The experiments also showed that biphenyl has to be hydroxylated and then conjugated before it appears in the rat bile. Thus, 5.2% of the dose was found in the 24 hrs bile as conjugates, mainly of 4–hydroxy–, 4,4′–dihydroxy– and 3,4,4′–trihydroxy–biphenyl. Faecal excretion of phenolic biphenyl derivatives was found to be of minor importance, but 4.7 % of the dose was detected during the first 24 hrs after dosing. The following previously undetected metabolites of biphenyl were found: 3,4′–dihydroxy–, 3,4,4′–trihydroxy–, 3,4′–dihydroxy–4–methoxy– and 4,4′–dihydroxy–3–methoxy–biphenyl.

Effect of natural and synthetic glucocorticoids on rat hepatic microsomal drug metabolism

Endogenous and synthetic glucocorticoids of varied biological potency have been used for the treatment of intact male rats in an attempt to determine the interactions of corticosteroids with hepatic mixed-function oxidation. The more potent synthetic steroids increased several components of the microsomal electron transport chain, and the metabolism of biphenyl, aniline, benzo[α]pyrene and ethylmorphine. In contrast, the natural glucocorticoids and their less potent synthetic analogues decreased or had no effect on the activity of these parameters. None of the steroids used affected the spectral interaction kinetics or the apparent K m values of the enzymes responsible for the metabolism of type I and type II substrates. The effects of glucocorticoids on hepatic drug metabolism therefore appear to be different from those of phenobarbital or 3-methylcholanthrene, but show some similarities with those resulting from pregnenolone-16α-carbonitrile or spironolactone pretreatment.

The metabolism of biphenyl by isolated viable rat hepatocytes.

1. The metabolism of biphenyl by isolated viable rat hepatocytes has been studied and a tentative scheme of metabolism proposed which involves initial hydroxylation at the 2- and 4-positions followed by conjugation and/or further hydroxylation of these primary metabolites. 2. Biphenyl was toxic to viable hepatocytes when used at a concentration approaching that used in conventional microsomal assay systems. 3. The production of small amounts of 4-hydroxybiphenyl appears to activate its subsequent conjugation. 4. The data presented in this paper integrate previous results obtained with cell fractions, and demonstrates the importance of the isolated, viable hepatocyte system as a model for total drug metabolism.

The circadian variation of hepatic microsomal drug and steroid metabolism in the golden hamster

Rhythmic variations in a number of parameters of hepatic microsomal drug and steroid metabolism and binding were observed in the adult male golden hamster. With an illumination schedule of a light phase between 06.30 and 18.30 h, maximal activities were encountered between 04.00 and 08.00 h with corresponding minima between 16.00 and 18.00 h. In addition, kinetic changes were observed in both the metabolism and spectral interaction of aniline and biphenyl at times of maximal and minimal activities. Possible mechanisms responsible for the circadian variation in hamster hepatic microsomal xenobiotic metabolism are discussed.

Biphenyl Hydroxylations and Spectrally Apparent Interactions with Liver Microsomes from Hamsters Pre-treated with Phenobarbitone and 3-Methylcholanthrene

1. Metabolism of [14-C]biphenyl by hamster liver microsomes has been studied by t.l.c., quantitative fluorimetry and difference absorption spectrophotometry. 2. 4-Hydroxybiphenyl (major metabolite) and 2-hydroxybiphenyl (minor) accounted for at least 83% of total biphenyl metabolism. Small quantities of 2,2'- and 4,4'-dihydroxybiphenyl metabolites were also tentatively identified. 3. Biphenyl 2- and 4-hydroxylations exhibited different NADPH-NADH specificities and pH profiles. 4. Phenobarbitone preferentially induced formation of 4-hydroxybiphenyl, while 3-methylcholanthrene induced 2- and 4-hydroxylation almost equally by affecting both production and further metabolism of 2- and 4-hydroxybiphenyl. 5. Biphenyl, 2- and 4-hydroxy- and 2,2'-dihydroxybiphenyl gave both high- and low-affinity type I spectrally apparent microsomal interactions, whereas 4,4'-dihydroxybiphenyl promoted a reverse type I spectral change. There was an inverse correlation between the spectral dissociation constants (Ks) and lipid solubilities for the low-affinity type I interactions and a possible direct correlation for the high-affinity type I interactions. 6. Phenobarbitone and 3-methylcholanthrene induced cytochrome P-450 and cytochrome P-448 respectively and produced complex changes in the biphenyl type I interaction kinetics. No direct relationship was found in 'control' or 'induced' microsomes between biphenyl 2- or 4-hydroxylation, the type I interaction and cytochrome P-450 concentration. The results are discussed in terms of a 3-methylcholanthrene-inducible biphenyl 2- and 4-hydroxylase and a phenobarbitone-inducible biphenyl 4-hydroxylase.

Metabolism of biphenyl. Structure and physicochemical properties of 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoic acid, the meta-cleavage product from 2,3-dihydroxybiphenyl by Pseudomonas putida.

The structure of 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoic acid for the meta-cleavage product of 2,3-dihydroxybiphenyl by a Pseudomonas putida strain was demonstrated on the basis of its chemical and physicochemical properties and those of its derivatives.

Metabolism of biphenyl. 2-Hydroxy-6-oxo-6-phenylhexa-2,4-dienoate: the meta-cleavage product from 2,3-dihydroxybiphenyl by Pseudomonas putida.

1. 2-Hydroxy-6-oxo-6-phenylhexa-2,4-dienoic acid was isolated and identified from washed suspensions of Pseudomonas putida incubated in the presence of 2,3-dihydroxybiphenyl. 2. Benzoic acid was isolated from reaction mixtures of crude cell-free extracts incubated with 2,3-dihydroxybiphenyl. 3. The presence in the same reaction mixtures of either 4-hydroxy-2-oxovalerate or 2-hydroxypenta-2,4-dienoate was suggested by mass spectrometry. 4. The degradative pathway of biphenyl is discussed.

The microbial metabolism of biphenyl.

The microbial metabolism of biphenyl.

625. Bipartite biphenyl metabolism: Creaven, P. J., Parke, D. V. & Williams, R. T. (1964). Differential stimulation of the o- and p-hydroxylation of biphenyl by liver microsomes. Biochem. J.91, 21 p

625. Bipartite biphenyl metabolism: Creaven, P. J., Parke, D. V. & Williams, R. T. (1964). Differential stimulation of the o- and p-hydroxylation of biphenyl by liver microsomes. Biochem. J.91, 21 p

Metabolism of Biphenyl and 4-Chlorobiphenyl in the Rabbit

Metabolism of Biphenyl and 4-Chlorobiphenyl in the Rabbit