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. 1996 Dec;104(Suppl 6):1123–1128. doi: 10.1289/ehp.961041123

Personal reflections on 50 years of study of benzene toxicology.

D V Parke 1
PMCID: PMC1469731  PMID: 9118881

Abstract

The metabolism of benzene is reviewed, and the objectives of a quantitative balance study begun in 1945 are outlined; problems of toxicology and metabolism research of some 50 years ago are considered. The quantitative metabolism of 14C-benzene in the rabbit is annotated and compared with that of unlabeled benzene quantified by nonisotopic methods. The anomalies of phenylmercapturic acid and trans-trans-muconic acid as metabolites of benzene are examined in detail by isotopic and nonisotopic methods; these compounds are true but minor metabolites of benzene. Oxygen radicals are involved in both the metabolism of benzene and its toxicity; the roles of CYP2E1, the redox cycling of quinone metabolites, glutathione oxidation, and oxidative stress in the unique radiomimetic, hematopoietic toxicity of benzene are discussed. Differences between the toxicity of benzene and the halobenzenes are related to fundamental differences in their electronic structures and to the consequent pathways of metabolic activation and detoxication.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. AZOUZ W. M., PARKE D. V., WILLIAMS R. T. Studies in detoxication, 42. Fluorobenzene: Spectrophotometric determination of the elimination of unchanged halogenobenzenes by rabbits; a comparison of the oxidation in vivo of fluorobenzene and of benzene. Biochem J. 1952 Mar;50(5):702–706. doi: 10.1042/bj0500702. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Johansson I., Ingelman-Sundberg M. Hydroxyl radical-mediated, cytochrome P-450-dependent metabolic activation of benzene in microsomes and reconstituted enzyme systems from rabbit liver. J Biol Chem. 1983 Jun 25;258(12):7311–7316. [PubMed] [Google Scholar]
  3. Kalf G. F., Schlosser M. J., Renz J. F., Pirozzi S. J. Prevention of benzene-induced myelotoxicity by nonsteroidal anti-inflammatory drugs. Environ Health Perspect. 1989 Jul;82:57–64. doi: 10.1289/ehp.898257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Latriano L., Goldstein B. D., Witz G. Formation of muconaldehyde, an open-ring metabolite of benzene, in mouse liver microsomes: an additional pathway for toxic metabolites. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8356–8360. doi: 10.1073/pnas.83.21.8356. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Lewis D. F., Ioannides C., Parke D. V. A retrospective evaluation of COMPACT predictions of the outcome of NTP rodent carcinogenicity testing. Environ Health Perspect. 1995 Feb;103(2):178–184. doi: 10.1289/ehp.95103178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Liu P. T., Ioannides C., Shavila J., Symons A. M., Parke D. V. Effects of ether anaesthesia and fasting on various cytochromes P450 of rat liver and kidney. Biochem Pharmacol. 1993 Feb 24;45(4):871–877. doi: 10.1016/0006-2952(93)90171-r. [DOI] [PubMed] [Google Scholar]
  7. Liu P. T., Ioannides C., Symons A. M., Parke D. V. Role of tissue glutathione in prevention of surgical trauma. Xenobiotica. 1993 Aug;23(8):899–911. doi: 10.3109/00498259309059417. [DOI] [PubMed] [Google Scholar]
  8. MacEachern L., Snyder R., Laskin D. L. Alterations in the morphology and functional activity of bone marrow phagocytes following benzene treatment of mice. Toxicol Appl Pharmacol. 1992 Dec;117(2):147–154. doi: 10.1016/0041-008x(92)90231-g. [DOI] [PubMed] [Google Scholar]
  9. Nerland D. E., Pierce W. M., Jr Identification of N-acetyl-S-(2,5-dihydroxyphenyl)-L-cysteine as a urinary metabolite of benzene, phenol, and hydroquinone. Drug Metab Dispos. 1990 Nov-Dec;18(6):958–961. [PubMed] [Google Scholar]
  10. PARKE D. V., WILLIAMS R. T. Studies in detoxication. 38. The metabolism of benzene: the determination of phenylmercapturic acid in urine; mercapturic acid excretion by rabbits receiving benzene. Biochem J. 1951 May;48(5):624–629. doi: 10.1042/bj0480624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. PARKE D. V., WILLIAMS R. T. Studies in detoxication. 44. The metabolism of benzene; the muconic acid excreted by rabbits receiving benzene; determination of the isomeric muconic acids. Biochem J. 1952 Jun;51(3):339–348. doi: 10.1042/bj0510339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. PARKE D. V., WILLIAMS R. T. Studies in detoxication. XLIX. The metabolism of benzene containing (14C1) benzene. Biochem J. 1953 May;54(2):231–238. doi: 10.1042/bj0540231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Parke D. V. The cytochromes P450 and mechanisms of chemical carcinogenesis. Environ Health Perspect. 1994 Oct;102(10):852–853. doi: 10.1289/ehp.94102852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Parke D. V., Williams R. T. Studies in detoxication. 30. The metabolism of benzene. (a) The determination of benzene. (b) The elimination of unchanged benzene by rabbits. Biochem J. 1950 Feb;46(2):236–243. doi: 10.1042/bj0460236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Robertson M. L., Eastmond D. A., Smith M. T. Two benzene metabolites, catechol and hydroquinone, produce a synergistic induction of micronuclei and toxicity in cultured human lymphocytes. Mutat Res. 1991 Jul;249(1):201–209. doi: 10.1016/0027-5107(91)90147-g. [DOI] [PubMed] [Google Scholar]
  16. SMITH J. N., SPENCER B., WILLIAMS R. T. Studies in detoxication; the metabolism of chlorobenzene in the rabbit; isolation of dihydrodihydroxychlorobenzene, p-chlorophenylglucuronide, 4-chlorocatechol glucuronide and p-chlorophenylmercapturic acid. Biochem J. 1950 Sep;47(3):284–293. doi: 10.1042/bj0470284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Schrenk D., Ingelman-Sundberg M., Bock K. W. Influence of P-4502E1 induction on benzene metabolism in rat hepatocytes and on biliary metabolite excretion. Drug Metab Dispos. 1992 Mar-Apr;20(2):137–141. [PubMed] [Google Scholar]
  18. Subrahmanyam V. V., Kolachana P., Smith M. T. Hydroxylation of phenol to hydroquinone catalyzed by a human myeloperoxidase-superoxide complex: possible implications in benzene-induced myelotoxicity. Free Radic Res Commun. 1991;15(5):285–296. doi: 10.3109/10715769109105224. [DOI] [PubMed] [Google Scholar]
  19. TURNER H. S. A convenient synthesis of carbon-labelled benzene. Nature. 1951 Jul 14;168(4263):73–74. doi: 10.1038/168073b0. [DOI] [PubMed] [Google Scholar]
  20. Tsutsumi M., Wang J. S., Takase S., Takada A. Hepatic messenger RNA contents of cytochrome P4502E1 in patients with different P4502E1 genotypes. Alcohol Alcohol Suppl. 1994;29(1):29–32. [PubMed] [Google Scholar]
  21. Zhang L., Robertson M. L., Kolachana P., Davison A. J., Smith M. T. Benzene metabolite, 1,2,4-benzenetriol, induces micronuclei and oxidative DNA damage in human lymphocytes and HL60 cells. Environ Mol Mutagen. 1993;21(4):339–348. doi: 10.1002/em.2850210405. [DOI] [PubMed] [Google Scholar]

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