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. 1990 Apr;85:31–41. doi: 10.1289/ehp.85-1568313

Pulmonary metabolism of foreign compounds: its role in metabolic activation.

G M Cohen 1
PMCID: PMC1568313  PMID: 2200668

Abstract

The lung has the potential of metabolizing many foreign chemicals to a vast array of metabolites with different pharmacological and toxicological properties. Because many chemicals require metabolic activation in order to exert their toxicity, the cellular distribution of the drug-metabolizing enzymes in a heterogeneous tissue, such as the lung, and the balance of metabolic activation and deactivation pathways in any particular cell are key factors in determining the cellular specificity of many pulmonary toxins. Environmental factors such as air pollution, cigarette smoking, and diet markedly affect the pulmonary metabolism of some chemicals and, thereby, possibly affect their toxicity.

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Selected References

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  1. AXELROD J. The enzymatic N-methylation of serotonin and other amines. J Pharmacol Exp Ther. 1962 Oct;138:28–33. [PubMed] [Google Scholar]
  2. Abdul-Karim R. W., Drucker M., Jacobs R. D. The influence of estradiol-17 beta on cholinesterase activity in the lung. Am J Obstet Gynecol. 1970 Dec 1;108(7):1098–1101. doi: 10.1016/0002-9378(70)90459-x. [DOI] [PubMed] [Google Scholar]
  3. Aitio A., Hartiala J., Uotila P. Glucuronide synthesis in the isolated perfused rat lung. Biochem Pharmacol. 1976 Aug 15;25(16):1919–1920. doi: 10.1016/0006-2952(76)90202-1. [DOI] [PubMed] [Google Scholar]
  4. Autrup H., Wefald F. C., Jeffrey A. M., Tate H., Schwartz R. D., Trump B. F., Harris C. C. Metabolism of benzo[a]pyrene by cultured tracheobronchial tissues from mice, rats, hamsters, bovines and humans. Int J Cancer. 1980 Feb 15;25(2):293–300. doi: 10.1002/ijc.2910250219. [DOI] [PubMed] [Google Scholar]
  5. Axelrod J., Daly J. Phenol-O-methyltransferase. Biochim Biophys Acta. 1968 Jul 9;159(3):472–478. doi: 10.1016/0005-2744(68)90131-9. [DOI] [PubMed] [Google Scholar]
  6. Bakhle Y. S., Vane J. R. Pharmacokinetic function of the pulmonary circulation. Physiol Rev. 1974 Oct;54(4):1007–1045. doi: 10.1152/physrev.1974.54.4.1007. [DOI] [PubMed] [Google Scholar]
  7. Baron J., Burke J. P., Guengerich F. P., Jakoby W. B., Voigt J. M. Sites for xenobiotic activation and detoxication within the respiratory tract: implications for chemically induced toxicity. Toxicol Appl Pharmacol. 1988 May;93(3):493–505. doi: 10.1016/0041-008x(88)90053-1. [DOI] [PubMed] [Google Scholar]
  8. Bartosek I., Mussini E., Saronio C., Garattini S. Studies on nitrazepam reduction in vitro. Eur J Pharmacol. 1970 Jul 15;11(2):249–253. doi: 10.1016/0014-2999(70)90054-3. [DOI] [PubMed] [Google Scholar]
  9. Bend J. R., Serabjit-Singh C. J., Philpot R. M. The pulmonary uptake, accumulation, and metabolism of xenobiotics. Annu Rev Pharmacol Toxicol. 1985;25:97–125. doi: 10.1146/annurev.pa.25.040185.000525. [DOI] [PubMed] [Google Scholar]
  10. Bickel M. H. Liver metabolic reactions: tertiary amine N-dealkylation, tertiary amine N-oxidation, N-oxide reduction, and N-oxide N-dealkylation. I. Tricyclic tertiary amine drugs. Arch Biochem Biophys. 1972 Jan;148(1):54–62. doi: 10.1016/0003-9861(72)90114-2. [DOI] [PubMed] [Google Scholar]
  11. Boyd M. R. Biochemical mechanisms in chemical-induced lung injury: roles of metabolic activation. Crit Rev Toxicol. 1980 Aug;7(2):103–176. doi: 10.3109/10408448009037487. [DOI] [PubMed] [Google Scholar]
  12. Boyd M. R. Evidence for the Clara cell as a site of cytochrome P450-dependent mixed-function oxidase activity in lung. Nature. 1977 Oct 20;269(5630):713–715. doi: 10.1038/269713a0. [DOI] [PubMed] [Google Scholar]
  13. Briant R. H., Blackwell E. W., Williams F. M., Davies D. S., Dollery C. T. The metabolism of sympathomimetic bronchodilator drugs by the isolated perfused dog lung. Xenobiotica. 1973 Dec;3(12):787–799. doi: 10.3109/00498257309151603. [DOI] [PubMed] [Google Scholar]
  14. Brown E. A. THe localization, metabolism and effects of drugs and toxicants in lung. Drug Metab Rev. 1974;3(1):33–87. doi: 10.3109/03602537408993738. [DOI] [PubMed] [Google Scholar]
  15. Burke M. D., Prough R. A., Mayer R. T. Characteristics of a microsomal cytochrome P-448-mediated reaction. Ethoxyresorufin O-de-ethylation. Drug Metab Dispos. 1977 Jan-Feb;5(1):1–8. [PubMed] [Google Scholar]
  16. Cantrell E., Busbee D., Warr G., Martin R., Anderson M. D. Induction of aryl hydrocarbon hydroxylase in human lymphocytes and pulmonary alveolar macrophages--a comparison. Life Sci. 1973 Dec 16;13(12):1649–1654. doi: 10.1016/0024-3205(73)90112-4. [DOI] [PubMed] [Google Scholar]
  17. Cohen G. M., Haws S. M., Moore B. P., Bridges J. W. Benzo(a)pyren-3-yl hydrogen sulphate, a major ethyl acetate-extractable metabolite of benzo(a)pyrene in human, hamster and rat lung cultures. Biochem Pharmacol. 1976 Dec 1;25(23):2561–2570. doi: 10.1016/0006-2952(76)90510-4. [DOI] [PubMed] [Google Scholar]
  18. Cohen G. M., Moore B. P. Metabolism of (3H)benzo(a)pyrene by different portions of the respiratory tract. Biochem Pharmacol. 1976 Jul 15;25(14):1623–1629. doi: 10.1016/0006-2952(76)90474-3. [DOI] [PubMed] [Google Scholar]
  19. Cohen G. M., Uotila P., Hartiala J., Suolinna E. M., Simberg N., Pelkonen O. Metabolism and covalent binding of [3H]benzo(a)pyrene by isolated perfused lungs and short-term tracheal organ culture of cigarette smoke-exposed rats. Cancer Res. 1977 Jul;37(7 Pt 1):2147–2155. [PubMed] [Google Scholar]
  20. Devereux T. R., Jones K. G., Bend J. R., Fouts J. R., Statham C. N., Boyd M. R. In vitro metabolic activation of the pulmonary toxin, 4-ipomeanol, in nonciliated bronchiolar epithelial (Clara) and alveolar type II cells isolated from rabbit lung. J Pharmacol Exp Ther. 1982 Jan;220(1):223–227. [PubMed] [Google Scholar]
  21. Grasso P., Williams M., Hodgson R., Wright M. G., Gangolli S. D. The histochemical distribution of aniline hydroxylase in rat tissues. Histochem J. 1971 Mar;3(2):117–126. doi: 10.1007/BF01003057. [DOI] [PubMed] [Google Scholar]
  22. Grover P. L., Hewer A., Sims P. K-region epoxides of polycyclic hydrocarbons: formation and further metabolism of benz (a) anthracene 5,6-oxide by human lung preparations. FEBS Lett. 1973 Aug 1;34(1):63–68. doi: 10.1016/0014-5793(73)80703-3. [DOI] [PubMed] [Google Scholar]
  23. Grover P. L., Hewer A., Sims P. Metabolism of polycyclic hydrocarbons by rat-lung preparations. Biochem Pharmacol. 1974 Jan 15;23(2):323–332. doi: 10.1016/0006-2952(74)90423-7. [DOI] [PubMed] [Google Scholar]
  24. Grover P. L. K-region epoxides of polycyclic hydrocarbons: formation and further metabolism by rat-lung preparations. Biochem Pharmacol. 1974 Jan 15;23(2):333–343. doi: 10.1016/0006-2952(74)90424-9. [DOI] [PubMed] [Google Scholar]
  25. Harris C. C., Autrup H., Connor R., Barrett L. A., McDowell E. M., Trump B. F. Interindividual variation in binding of benzo[a]pyrene to DNA in cultured human bronchi. Science. 1976 Dec 3;194(4269):1067–1069. doi: 10.1126/science.982061. [DOI] [PubMed] [Google Scholar]
  26. Harris C. C., Hsu I. C., Stoner G. D., Trump B. F., Selkirk J. K. Human pulmonary alveolar macrophages metabolise benzo(a)pyrene to proximate and ultimate mutagens. Nature. 1978 Apr 13;272(5654):633–634. doi: 10.1038/272633a0. [DOI] [PubMed] [Google Scholar]
  27. Haschek W. M., Hakkinen P. J., Witschi H. P., Hanzlik R. P., Traiger G. J. Nonciliated bronchiolar epithelial (Clara) cell necrosis induced by organometallic carbonyl compounds. Toxicol Lett. 1982 Nov;14(1-2):85–92. doi: 10.1016/0378-4274(82)90013-3. [DOI] [PubMed] [Google Scholar]
  28. KIESE M., UEHLEKE H., WEGER N. [Extraerythrocytic influences of phenylhydroxylamine and nitrosobenzene on hemoglobin formation in the red cells]. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol. 1961;242:130–133. [PubMed] [Google Scholar]
  29. Law F. C., Eling T. E., Bend J. R., Fouts J. R. Metabolism of xenobiotics by the isolated perfused lung. Comparison with in vitro incubations. Drug Metab Dispos. 1974 Sep-Oct;2(5):433–442. [PubMed] [Google Scholar]
  30. Leibman K. C. Reduction of ketones in liver cytosol. Xenobiotica. 1971 Jan;1(1):97–104. doi: 10.3109/00498257109044382. [DOI] [PubMed] [Google Scholar]
  31. Marnett L. J. Polycyclic aromatic hydrocarbon oxidation during prostaglandin biosynthesis. Life Sci. 1981 Aug 10;29(6):531–546. doi: 10.1016/0024-3205(81)90431-8. [DOI] [PubMed] [Google Scholar]
  32. Mehendale H. M., El-Bassiouni E. A. Uptake and disposition of aldrin and dieldrin by isolated perfused rabbit lung. Drug Metab Dispos. 1975 Nov-Dec;3(6):543–556. [PubMed] [Google Scholar]
  33. Mehta R., Cohen G. M. Major differences in the extent of conjugation with glucuronic acid and sulphate in human peripheral lung. Biochem Pharmacol. 1979 Aug 15;28(16):2479–2484. doi: 10.1016/0006-2952(79)90011-x. [DOI] [PubMed] [Google Scholar]
  34. Miller E. C., Miller J. A. Searches for ultimate chemical carcinogens and their reactions with cellular macromolecules. Cancer. 1981 May 15;47(10):2327–2345. doi: 10.1002/1097-0142(19810515)47:10<2327::aid-cncr2820471003>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
  35. Minchin R. F., Boyd M. R. Localization of metabolic activation and deactivation systems in the lung: significance to the pulmonary toxicity of xenobiotics. Annu Rev Pharmacol Toxicol. 1983;23:217–238. doi: 10.1146/annurev.pa.23.040183.001245. [DOI] [PubMed] [Google Scholar]
  36. Moore B. P., Cohen G. M. Metabolism of benzo(a)pyrene and its major metabolites to ethyl acetate-soluble and water-soluble metabolites by cultured rodent trachea. Cancer Res. 1978 Sep;38(9):3066–3075. [PubMed] [Google Scholar]
  37. Palmer M. S., Exley R. W., Coffin D. L. Influence of pollutant gases on benzpyrene hydroxylase activity. Arch Environ Health. 1972 Dec;25(6):439–442. doi: 10.1080/00039896.1972.10666200. [DOI] [PubMed] [Google Scholar]
  38. Ravindranath V., Burka L. T., Boyd M. R. Reactive metabolites from the bioactivation of toxic methylfurans. Science. 1984 May 25;224(4651):884–886. doi: 10.1126/science.6719117. [DOI] [PubMed] [Google Scholar]
  39. Reid W. D., Glick J. M., Krishna G. Metabolism of foreign compounds by alveolar macrophages of rabbits. Biochem Biophys Res Commun. 1972 Nov 1;49(3):626–634. doi: 10.1016/0006-291x(72)90457-3. [DOI] [PubMed] [Google Scholar]
  40. Rosenbloom P. M., Bass A. D. A lung perfusion preparation for the study of drug metabolism. J Appl Physiol. 1970 Jul;29(1):138–144. doi: 10.1152/jappl.1970.29.1.138. [DOI] [PubMed] [Google Scholar]
  41. Serabjit-Singh C. J., Nishio S. J., Philpot R. M., Plopper C. G. The distribution of cytochrome P-450 monooxygenase in cells of the rabbit lung: an ultrastructural immunocytochemical characterization. Mol Pharmacol. 1988 Mar;33(3):279–289. [PubMed] [Google Scholar]
  42. Serabjit-Singh C. J., Wolf C. R., Philpot R. M., Plopper C. G. Cytochrome p-450: localization in rabbit lung. Science. 1980 Mar 28;207(4438):1469–1470. doi: 10.1126/science.6767272. [DOI] [PubMed] [Google Scholar]
  43. Sims P., Grover P. L. Epoxides in polycyclic aromatic hydrocarbon metabolism and carcinogenesis. Adv Cancer Res. 1974;20:165–274. doi: 10.1016/s0065-230x(08)60111-6. [DOI] [PubMed] [Google Scholar]
  44. Sims P., Grover P. L., Swaisland A., Pal K., Hewer A. Metabolic activation of benzo(a)pyrene proceeds by a diol-epoxide. Nature. 1974 Nov 22;252(5481):326–328. doi: 10.1038/252326a0. [DOI] [PubMed] [Google Scholar]
  45. Sivarajah K., Lasker J. M., Eling T. E. Prostaglandin synthetase-dependent cooxidation of (+/-)-benzo(a)pyrene-7,8-dihydrodiol by human lung and other mammalian tissues. Cancer Res. 1981 May;41(5):1834–1839. [PubMed] [Google Scholar]
  46. Wattenberg L. W. Dietary modification of intestinal and pulmonary aryl hydrocarbon hydroxylase activity. Toxicol Appl Pharmacol. 1972 Dec;23(4):741–748. doi: 10.1016/0041-008x(72)90115-9. [DOI] [PubMed] [Google Scholar]
  47. Welch R. M., Cavallito J., Loh A. Effect of exposure to cigarette smoke on the metabolism of benzo(a)pyrene and acetophenetidin by lung and intestine of rats. Toxicol Appl Pharmacol. 1972 Dec;23(4):749–758. doi: 10.1016/0041-008x(72)90116-0. [DOI] [PubMed] [Google Scholar]
  48. Whitnack E., Knapp D. R., Holmes J. C., Fowler N. O., Gaffney T. E. Demethylation of nortriptyline by the dog lung. J Pharmacol Exp Ther. 1972 May;181(2):288–291. [PubMed] [Google Scholar]

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