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. 1988 Sep;43(3):280–284.

The gene CYP3 encoding P450pcn1 (nifedipine oxidase) is tightly linked to the gene COL1A2 encoding collagen type 1 alpha on 7q21-q22.1.

B A Brooks 1, O W McBride 1, C T Dolphin 1, M Farrall 1, P J Scambler 1, F J Gonzalez 1, J R Idle 1
PMCID: PMC1715388  PMID: 2901225

Abstract

CYP3, the gene which encodes the hepatic cytochrome P450pcn1, the isozyme responsible for the metabolic oxidation of the calcium channel-blocking drug nifedipine, has recently been mapped to human chromosome 7 using somatic cell hybrids. Using multilocus linkage analysis in CEPH families, we examined the linkage of a cDNA probe (hPCN1) for CYP3 to the oncogene MET, the pro-alpha 2(1) collagen gene COL1A2, and the T-cell receptor beta-chain gene TCRB, together with three arbitrary loci D7S8, D7S13, and D7S16, defined by the anonymous DNA probes pJ3.11, pB79a, and p7C22, respectively. From 70 CEPH parents screened with a StyI RFLP for hPCN1, four informative families were found each with both parental and maternal grandparents and 6-11 children per family. Tight linkage emerged between CYP3 and COL1A2, with a maximum combined lod score of 5.72 at theta = 0, suggesting the most likely subchromosomal localization of CYP3 is 7q21.3-q22.1.

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Selected References

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

  1. Beaune P. H., Umbenhauer D. R., Bork R. W., Lloyd R. S., Guengerich F. P. Isolation and sequence determination of a cDNA clone related to human cytochrome P-450 nifedipine oxidase. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8064–8068. doi: 10.1073/pnas.83.21.8064. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Dayer P., Kronbach T., Eichelbaum M., Meyer U. A. Enzymatic basis of the debrisoquine/sparteine-type genetic polymorphism of drug oxidation. Characterization of bufuralol 1'-hydroxylation in liver microsomes of in vivo phenotyped carriers of the genetic deficiency. Biochem Pharmacol. 1987 Dec 1;36(23):4145–4152. doi: 10.1016/0006-2952(87)90573-9. [DOI] [PubMed] [Google Scholar]
  3. Eichelbaum M. Polymorphic drug oxidation in humans. Fed Proc. 1984 May 15;43(8):2298–2302. [PubMed] [Google Scholar]
  4. Eichelbaum M., Spannbrucker N., Steincke B., Dengler H. J. Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Eur J Clin Pharmacol. 1979 Sep;16(3):183–187. doi: 10.1007/BF00562059. [DOI] [PubMed] [Google Scholar]
  5. Evans D. A., Harmer D., Downham D. Y., Whibley E. J., Idle J. R., Ritchie J., Smith R. L. The genetic control of sparteine and debrisoquine metabolism in man with new methods of analysing bimodal distributions. J Med Genet. 1983 Oct;20(5):321–329. doi: 10.1136/jmg.20.5.321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Evans D. A., Mahgoub A., Sloan T. P., Idle J. R., Smith R. L. A family and population study of the genetic polymorphism of debrisoquine oxidation in a white British population. J Med Genet. 1980 Apr;17(2):102–105. doi: 10.1136/jmg.17.2.102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Feinberg A. P., Vogelstein B. "A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity". Addendum. Anal Biochem. 1984 Feb;137(1):266–267. doi: 10.1016/0003-2697(84)90381-6. [DOI] [PubMed] [Google Scholar]
  8. Freymann D. M., Metcalf P., Turner M., Wiley D. C. 6 A-resolution X-ray structure of a variable surface glycoprotein from Trypanosoma brucei. Nature. 1984 Sep 13;311(5982):167–169. doi: 10.1038/311167a0. [DOI] [PubMed] [Google Scholar]
  9. Gonzalez F. J., Schmid B. J., Umeno M., Mcbride O. W., Hardwick J. P., Meyer U. A., Gelboin H. V., Idle J. R. Human P450PCN1: sequence, chromosome localization, and direct evidence through cDNA expression that P450PCN1 is nifedipine oxidase. DNA. 1988 Mar;7(2):79–86. doi: 10.1089/dna.1988.7.79. [DOI] [PubMed] [Google Scholar]
  10. Gonzalez F. J., Skoda R. C., Kimura S., Umeno M., Zanger U. M., Nebert D. W., Gelboin H. V., Hardwick J. P., Meyer U. A. Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature. 1988 Feb 4;331(6155):442–446. doi: 10.1038/331442a0. [DOI] [PubMed] [Google Scholar]
  11. Gonzalez F. J., Song B. J., Hardwick J. P. Pregnenolone 16 alpha-carbonitrile-inducible P-450 gene family: gene conversion and differential regulation. Mol Cell Biol. 1986 Aug;6(8):2969–2976. doi: 10.1128/mcb.6.8.2969. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Idle J. R., Smith R. L. Polymorphisms of oxidation at carbon centers of drugs and their clinical significance. Drug Metab Rev. 1979;9(2):301–317. doi: 10.3109/03602537908993896. [DOI] [PubMed] [Google Scholar]
  13. Kaisary A., Smith P., Jaczq E., McAllister C. B., Wilkinson G. R., Ray W. A., Branch R. A. Genetic predisposition to bladder cancer: ability to hydroxylate debrisoquine and mephenytoin as risk factors. Cancer Res. 1987 Oct 15;47(20):5488–5493. [PubMed] [Google Scholar]
  14. Kleinbloesem C. H., van Brummelen P., Faber H., Danhof M., Vermeulen N. P., Breimer D. D. Variability in nifedipine pharmacokinetics and dynamics: a new oxidation polymorphism in man. Biochem Pharmacol. 1984 Nov 15;33(22):3721–3724. doi: 10.1016/0006-2952(84)90165-5. [DOI] [PubMed] [Google Scholar]
  15. Küpfer A., Preisig R. Inherited defects of hepatic drug metabolism. Semin Liver Dis. 1983 Nov;3(4):341–354. doi: 10.1055/s-2008-1040786. [DOI] [PubMed] [Google Scholar]
  16. Lathrop G. M., Farrall M., O'Connell P., Wainwright B., Leppert M., Nakamura Y., Lench N., Kruyer H., Dean M., Park M. Refined linkage map of chromosome 7 in the region of the cystic fibrosis gene. Am J Hum Genet. 1988 Jan;42(1):38–44. [PMC free article] [PubMed] [Google Scholar]
  17. Lathrop G. M., Lalouel J. M., Julier C., Ott J. Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci U S A. 1984 Jun;81(11):3443–3446. doi: 10.1073/pnas.81.11.3443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. 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]
  19. Molowa D. T., Schuetz E. G., Wrighton S. A., Watkins P. B., Kremers P., Mendez-Picon G., Parker G. A., Guzelian P. S. Complete cDNA sequence of a cytochrome P-450 inducible by glucocorticoids in human liver. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5311–5315. doi: 10.1073/pnas.83.14.5311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Nebert D. W., Gonzalez F. J. P450 genes: structure, evolution, and regulation. Annu Rev Biochem. 1987;56:945–993. doi: 10.1146/annurev.bi.56.070187.004501. [DOI] [PubMed] [Google Scholar]
  21. White R., Woodward S., Leppert M., O'Connell P., Hoff M., Herbst J., Lalouel J. M., Dean M., Vande Woude G. A closely linked genetic marker for cystic fibrosis. 1985 Nov 28-Dec 4Nature. 318(6044):382–384. doi: 10.1038/318382a0. [DOI] [PubMed] [Google Scholar]

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