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British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 1985 Jun;19(6):721–729. doi: 10.1111/j.1365-2125.1985.tb02706.x

Attempts to phenotype human liver samples in vitro for debrisoquine 4-hydroxylase activity.

A R Boobis, C E Hampden, S Murray, P Beaune, D S Davies
PMCID: PMC1463883  PMID: 4027115

Abstract

Twenty-eight samples of human liver have been characterised for cytochrome P-450 content, aldrin epoxidase, debrisoquine 4-hydroxylase and bufuralol 1'-hydroxylase activities. Evidence is presented here and elsewhere that bufuralol 1'-hydroxylase and debrisoquine 4-hydroxylase are activities catalysed by the same form of cytochrome P-450 in man, and that this form is different from that catalysing the epoxidation of aldrin. Attempts to phenotype liver samples in vitro, in the absence of any metabolic data in vivo for debrisoquine 4-hydroxylation status, met with limited success. A combination of enzyme assays will most probably be required in any such phenotyping of human liver samples.

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Selected References

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  1. Boobis A. R., Brodie M. J., Kahn G. C., Fletcher D. R., Saunders J. H., Davies D. S. Monooxygenase activity of human liver in microsomal fractions of needle biopsy specimens. Br J Clin Pharmacol. 1980 Jan;9(1):11–19. doi: 10.1111/j.1365-2125.1980.tb04790.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Boobis A. R., Davies D. S. Human cytochromes P-450. Xenobiotica. 1984 Jan-Feb;14(1-2):151–185. doi: 10.3109/00498258409151404. [DOI] [PubMed] [Google Scholar]
  3. Boobis A. R., Murray S., Hampden C. E., Davies D. S. Genetic polymorphism in drug oxidation: in vitro studies of human debrisoquine 4-hydroxylase and bufuralol 1'-hydroxylase activities. Biochem Pharmacol. 1985 Jan 1;34(1):65–71. doi: 10.1016/0006-2952(85)90101-7. [DOI] [PubMed] [Google Scholar]
  4. Boobis A. R., Murray S., Kahn G. C., Robertz G. M., Davies D. S. Substrate specificity of the form of cytochrome P-450 catalyzing the 4-hydroxylation of debrisoquine in man. Mol Pharmacol. 1983 Mar;23(2):474–481. [PubMed] [Google Scholar]
  5. Brodie M. J., Boobis A. R., Bulpitt C. J., Davies D. S. Influence of liver disease and environmental factors on hepatic monooxygenase activity in vitro. Eur J Clin Pharmacol. 1981;20(1):39–46. doi: 10.1007/BF00554665. [DOI] [PubMed] [Google Scholar]
  6. Dannan G. A., Guengerich F. P., Kaminsky L. S., Aust S. D. Regulation of cytochrome P-450. Immunochemical quantitation of eight isozymes in liver microsomes of rats treated with polybrominated biphenyl congeners. J Biol Chem. 1983 Jan 25;258(2):1282–1288. [PubMed] [Google Scholar]
  7. Davies D. S., Kahn G. C., Murray S., Brodie M. J., Boobis A. R. Evidence for an enzymatic defect in the 4-hydroxylation of debrisoquine by human liver. Br J Clin Pharmacol. 1981 Jan;11(1):89–91. doi: 10.1111/j.1365-2125.1981.tb01108.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dayer P., Balant L., Courvoisier F., Kupfer A., Kubli A., Gorgia A., Fabre J. The genetic control of bufuralol metabolism in man. Eur J Drug Metab Pharmacokinet. 1982 Jan-Mar;7(1):73–77. doi: 10.1007/BF03189547. [DOI] [PubMed] [Google Scholar]
  9. Jakobsson S. W., Okita R. T., Mock N. I., Masters B. S., Buja L. M., Prough R. A. Monooxygenase activities of human liver, lung, and kidney microsomes - a study of 42 post mortem cases. Acta Pharmacol Toxicol (Copenh) 1982 May;50(5):332–341. doi: 10.1111/j.1600-0773.1982.tb00984.x. [DOI] [PubMed] [Google Scholar]
  10. Kahn G. C., Boobis A. R., Murray S., Brodie M. J., Davies D. S. Assay and characterisation of debrisoquine 4-hydroxylase activity of microsomal fractions of human liver. Br J Clin Pharmacol. 1982 May;13(5):637–645. doi: 10.1111/j.1365-2125.1982.tb01430.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kapitulnik J., Popper P. J., Conney A. H. Comparative metabolism of benzo[a]pyrene and drugs in human liver. Clin Pharmacol Ther. 1977 Feb;21(2):166–176. doi: 10.1002/cpt1977212166. [DOI] [PubMed] [Google Scholar]
  12. Kremers P., Beaune P., Cresteil T., de Graeve J., Columelli S., Leroux J. P., Gielen J. E. Cytochrome P-450 monooxygenase activities in human and rat liver microsomes. Eur J Biochem. 1981 Sep 1;118(3):599–606. doi: 10.1111/j.1432-1033.1981.tb05561.x. [DOI] [PubMed] [Google Scholar]
  13. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  14. Mahgoub A., Idle J. R., Dring L. G., Lancaster R., Smith R. L. Polymorphic hydroxylation of Debrisoquine in man. Lancet. 1977 Sep 17;2(8038):584–586. doi: 10.1016/s0140-6736(77)91430-1. [DOI] [PubMed] [Google Scholar]
  15. Meier P. J., Mueller H. K., Dick B., Meyer U. A. Hepatic monooxygenase activities in subjects with a genetic defect in drug oxidation. Gastroenterology. 1983 Sep;85(3):682–692. [PubMed] [Google Scholar]
  16. Minder E. I., Meier P. J., Müller H. K., Minder C., Meyer U. A. Bufuralol metabolism in human liver: a sensitive probe for the debrisoquine-type polymorphism of drug oxidation. Eur J Clin Invest. 1984 Jun;14(3):184–189. doi: 10.1111/j.1365-2362.1984.tb01121.x. [DOI] [PubMed] [Google Scholar]
  17. Montgomery M. R., Rubin R. J. Oxygenation during inhibition of drug metabolism by carbon monoxide or hypoxic hypoxia. J Appl Physiol. 1973 Oct;35(4):505–509. doi: 10.1152/jappl.1973.35.4.505. [DOI] [PubMed] [Google Scholar]
  18. Newman S. L., Guzelian P. S. Identification of the cyanopregnenolone-inducible form of hepatic cytochrome P-450 as a catalyst of aldrin epoxidation. Biochem Pharmacol. 1983 May 1;32(9):1529–1531. doi: 10.1016/0006-2952(83)90477-x. [DOI] [PubMed] [Google Scholar]
  19. Pelkonen O., Sotaniemi E., Tokola O., Ahokas J. T. Correlations between cytochrome P-450 and oxidative metabolism of benzo[a]pyrene and 7-ethoxycoumarin in human liver in vitro and antipyrine elimination in vivo. Drug Metab Dispos. 1980 Jul-Aug;8(4):218–222. [PubMed] [Google Scholar]
  20. Wilson J. T., Spelsberg T. C. Growth hormone and drug metabolism. Acute effects on microsomal mixed-function oxidase activities in rat liver. Biochem J. 1976 Feb 15;154(2):433–438. doi: 10.1042/bj1540433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Wolff T., Deml E., Wanders H. Aldrin epoxidation, a highly sensitive indicator specific for cytochrome P-450-dependent mono-oxygenase activities. Drug Metab Dispos. 1979 Sep-Oct;7(5):301–305. [PubMed] [Google Scholar]
  22. von Bahr C., Groth C. G., Jansson H., Lundgren G., Lind M., Glaumann H. Drug metabolism in human liver in vitro: establishment of a human liver bank. Clin Pharmacol Ther. 1980 Jun;27(6):711–725. doi: 10.1038/clpt.1980.102. [DOI] [PubMed] [Google Scholar]

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