The fate of diphenyl in the rat

doi:10.1016/0003-9861(56)90390-3

Archives of Biochemistry and Biophysics

Volume 60, Issue 1, January 1956, Pages 14-20

https://doi.org/10.1016/0003-9861(56)90390-3 Get rights and content

Abstract

1.
1. A study of the fate of diphenyl in the rat has been carried out.
2.
2. Five metabolites, including 4-hydroxydiphenyl, 4-phenylcatechol, 4,4′-dihydroxydiphenyl, diphenylmercapturic acid and p-β-d-glucu-ronosidodiphenyl have been isolated from the urines of these animals.
3.
3. The role of sulfur in the metabolism of aromatic hydrocarbons is discussed.

References (7)

H.D. West et al.
J. Biol. Chem
(1951)
H.D. West et al.
H.D. West et al.

There are more references available in the full text version of this article.

Cited by (48)

The application of in vitro data in the derivation of the acceptable daily intake of food additives
1999, Food and Chemical Toxicology
The acceptable daily intake (ADI) for food additives is commonly derived from the NOAEL (no-observed-adverse-effect level) in long-term animal in vivo studies. To derive an ADI a safety or uncertainty factor (commonly 100) is applied to the NOAEL in the most sensitive test species. The 100-fold safety factor is considered to be the product of both species and inter-individual differences in toxicokinetics and toxicodynamics. Although in vitro data have previously been considered during the risk assessment of food additives, they have generally had no direct influence on the calculation of ADI values. In this review 18 food additives are evaluated for the availability of in vitro toxicity data which might be used for the derivation of a specific data-derived uncertainty factor. For the majority of the food additives reviewed, additional in vitro tests have been conducted which supplement and support the short- and long-term in vivo toxicity studies. However, it was recognized that these in vitro studies could not be used in isolation to derive an ADI; only when sufficient in vivo mechanistic data are available can such information be used in a regulatory context. Additional short-term studies are proposed for the food additives which, if conducted, would provide data that could then be used for the calculation of data-derived uncertainty factors.
In vivo genotoxicity of ortho-phenylphenol, biphenyl, and thiabendazole detected in multiple mouse organs by the alkaline single cell gel electrophoresis assay
1997, Mutation Research - Genetic Toxicology and Environmental Mutagenesis
In Japan, ortho-phenylphenol (OPP), biphenyl (BP), and thiabendazole (2-(4'-thiazolyl)benzimidazole, TBZ) are commonly used as a postharvest treatment to preserve imported citrus fruits during transport and storage. We used a modification of the alkaline single cell gel electrophoresis (SCG) (Comet) assay to test the in vivo genotoxicity of those agents in mouse stomach, liver, kidney, bladder, lung, brain, and bone marrow. CD-1 male mice were sacrificed 3, 8, and 24 h after oral administration of the test compounds. OPP (2000 mg/kg) induced DNA damage in the stomach, liver, kidney, bladder, and lung, BP (2000 mg/kg) and TBZ (200 mg/kg) induced DNA damage in all the organs studied. For OPP, increased DNA damage peaked at 3–8 h and tended to decrease at 24 h. For BP, on the contrary, increased DNA migration peaked at 24 h. That delay may have been due to the fact that OPP is metabolized by cytochrome 450 and prostaglandin H synthase to phenylbenzoquinone (PBQ), a DNA binding metabolite, and BP is metabolized to PBQ via OPP and m-phenylphenol. The positive response to TBZ, an aneugen, supports the in vivo DNA-damaging action of TBZ.
Microsomal oxidation of bromo-, chloro- and fluorobiphenyls
1993, Comparative Biochemistry and Physiology. Part C, Comparative
1. The metabolism of 2-, 3-, 4-bromo-, 2-, 4-chloro-, and 2-fluorobiphenyl by hepatic microsomes isolated from control and Aroclor 1254-treated rats and pigeons was studied.
2. Meta and para as well as dihydroxylated metabolites were detected, but para hydroxylation was the preferred route of metabolism with all of the substrates used.
3. The overall rates of hydroxylation were greater with hepatic microsomes from rats than from pigeons.
4. Treatment with Aroclor 1254, a potent inducer of hepatic monooygenases, resulted in increased rates of metabolism and in the enhanced formation of diol metabolites. Metabolism of halobiphenyls by induced P450 isoenzymes altered the regioselective hydroxylation pathways.
5. Ortho- and meta halosubstituted biphenyls were less rapidly metabolised when compared with paru substituted isomers.
Cytotoxic effects of biphenyl and hydroxybiphenyls on isolated rat hepatocytes
1993, Biochemical Pharmacology
The cytotoxic effects of biphenyl (BP) and its hydroxylated derivatives, o-phenylphenol (OPP), m-phenylphenol (MPP), p-phenylphenol (PPP), 2-biphenylyl glycidyl ether (OPP-epoxide), phenyl-hydroquinone (PHQ), o, o′-biphenol (o, o′-BPol) and p, p′-biphenol (p, p′-BPol), were investigated in freshly isolated rat hepatocytes. OPP, MPP and PPP, at concentration of 0.75 mM, resulted in the loss of intracellular ATP, glutathione (GSH) and protein thiols, causing cell death. OPP-epoxide and BP were less toxic than the OPP isomers. MPP or PPP compared with OPP caused serious impairments in oxidative phosphorylation in mitochondria isolated from rat liver. PHQ (0.75 mM) caused a rapid loss of intracellular ATP which preceded the onset of cell death. PHQ was more toxic than o, o′-BPol or p, p′-BPol. PHQ dissolved in Krebs-Henseleit buffer without hepatocytes was rapidly converted to its corresponding quinone, phenyl-benzoquinone. The cytotoxicity produced by PHQ depends on the rate of formation of reactive intermediates. These results indicate that the addition of a hydroxyl group to the aromatic ring of BP enhances BP-induced cytotoxicity and that the mitochondria are a common target of the OPP isomers and other BP derivatives. In addition, the para- or meta-hydroxyl groups rather than the ortho-hydroxyl group increase the toxicity. The cytotoxicity produced by PHQ depends on the rate of formation of reactive intermediate(s) such as phenyl-benzoquinone.
Changes in urine composition, bladder epithelial morphology, and DNA synthesis in male F344 rats in response to ingestion of bladder tumor promoters
1989, Toxicology and Applied Pharmacology
An investigation of changes in urine composition, morphology of bladder epithelium, and levels of DNA synthesis following 4 or 8 weeks oral administration of bladder tumor promoters or analogs without promotion potential was performed. The sodium salts of l-ascorbate, o-phenylphenate, and bicarbonate increased the pH value, sodium content, volume, and MgNH₄PO₄ crystalluria of the urine, while the parent compounds, l-ascorbic acid and o-phenylphenol, which in contrast are not tumor promoters, did not induce these changes. Sodium chloride ingestion caused natriuresis without increasing urinary pH. Diphenyl administration produced only microcalculi consisting of p-phenylphenol. Treatment with the antioxidants butylated hydroxytoluene, butylated hydroxyanisole, and ethoxyquin was also not associated with any changes in urinary pH or Na ions. However, tert-butylhydroquinone did cause an increase in pH. Administration of the strong bladder carcinogens N-butyl-N-(4-hydroxybutyl)nitrosamine and N-ethyl-N-(4-hydroxybutyl)nitrosamine did not result in alteration of urine composition, with the exception of a decrease in phosphorus concentration. However, all the bladder promoters and carcinogens, without exception, brought about an elevation of DNA synthesis in the urothelium and produced morphologic surface alterations such as formation of pleomorphic or short, uniform microvilli and ropy or leafy microridges. Thus, an ability to induce proliferation and cell surface alterations was characteristic of the complete range of bladder promoters investigated. The results suggest that considerable variation in the mechanisms underlying these changes may be involved for different individuals or groups of agents.
Promoting effects of various agents in rat urinary bladder carcinogenesis initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine
1986, Cancer Letters
The effects of various chemicals on the development of neoplastic lesions in the urinary bladder were investigated in male F344 rats given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) as an initiator in their drinking water for 4 weeks. The compounds tested, indomethacin, acemetacin, ε-aminocaproic acid (EACA), diphenyl, allopurinol and acetaminophen (AAP), were added to the diet or drinking water for 32 weeks, and all animals were killed at the end of week 36. Of the chemicals tested, only diphenyl significantly increased the incidences and average numbers (per 10 cm basement membrane) of papillary or nodular hyperplasias (PN hyperplasia), papillomas and carcinomas of the urinary bladder over those in animals treated with BBN alone. These findings show that diphenyl is a promoter of urinary bladder carcinogenesis in male F344 rats.

View all citing articles on Scopus

^☆

Presented at the Forty-sixth Annual Meeting of the American Society of Biological Chemists at San Francisco, California, April 11–15, 1955.

This study was aided by Research Grant C-1524 from the National Cancer Institute.

View full text

The fate of diphenyl in the rat☆

Abstract

J. Biol. Chem