Drug metabolism in human brain: High levels of cytochrome P4503A43 in brain and metabolism of anti-anxiety drug alprazolam to its active metabolite

PLoS ONE

Volumn 3, Issue 6, 2008, Pages

  Agarwal, Varsha ^a   Kommaddi, Reddy P ^a   Valli, Khader ^a   Ryder, Daniel ^b   Hyde, Thomas M ^c   Kleinman, Joel E ^c   Strobel, Henry W ^b   Ravindranath, Vijayalakshmi ^a  

^a NATIONAL BRAIN RESEARCH CENTRE   (India)

^b UNIVERSITY OF TEXAS MEDICAL SCHOOL   (United States)

^c Intramural Research Program   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 HYDROXYALPRAZOLAM; ALPHA HYDROXYALPRAZOLAM; ALPRAZOLAM; CYTOCHROME P450; CYTOCHROME P450 3A4; CYTOCHROME P450 3A43; DRUG METABOLITE; MESSENGER RNA; ANXIOLYTIC AGENT; CYP3A43 PROTEIN, HUMAN; UNSPECIFIC MONOOXYGENASE;

ADOLESCENT; ADULT; AGED; ANIMAL CELL; ARTICLE; BRAIN LEVEL; BRAIN METABOLISM; CONTROLLED STUDY; CORRELATION FUNCTION; DRUG METABOLISM; ETHNICITY; FEMALE; GENE EXPRESSION; HUMAN; HUMAN TISSUE; LIVER LEVEL; MALE; NONHUMAN; PHARMACODYNAMICS; PROTEIN FUNCTION; SCHOOL CHILD; BRAIN; ENZYMOLOGY; FLUORESCENCE IN SITU HYBRIDIZATION; GENETICS; METABOLISM; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION;

ALPRAZOLAM; ANTI-ANXIETY AGENTS; ARYL HYDROCARBON HYDROXYLASES; BRAIN; HUMANS; IN SITU HYBRIDIZATION, FLUORESCENCE; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; RNA, MESSENGER;

EID: 48649108684     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0002337     Document Type: Article

References (27)

1. Meyer RP, Gehlhaus M, Knoth R, Volk B (2007) Expression and function of cytochrome P450 in brain drug metabolism. Curr Drug Metab 4: 297-306.
2. Haining RL, Nichols HM (2007) Cytochrome P450-catalyzed pathways in human brain: metabolism meets pharmacology or old drugs with new mechanism of action? Pharmacol Ther 3: 537-545.
3. Anandatheerthavarada HK, Shankar SK, Ravindranath V (1990) Rat brain cytochromes P-450: catalytic, immunochemical properties and inducibility of multiple forms. Brain Res 536: 339-343.
4. Pai HV, Upadhya SC, Chinta SJ, Hedge SN, Ravindranath V (2002) Differential metabolism or alprazolam by liver and brain cytochrome (P4503A) to pharmacologically active metabolite. Pharmacogenomics J 2: 243-258.
5. Ravindranath V, Anandatheerthavarada HK, Shankar SK (1989) Xenobiotic metabolism in human brain-presence of cytochrome P-450 and associated mono-oxygenases in human brain regions. Brain Res 496: 331-335.
6. Kommaddi RP, Turman CM, Moorthy B, Wang L, Strobel HW, et al. (2007) An alternatively spliced cytochrome P4501A1 in human brain fails to bioactivate polycyclic aromatic hydrocarbons to DNA-reactive metabolites. J Neurochem 102: 867-877.
7. Ravindranath V, Kommaddi RP, Pai HV (2006) Unique cytochromes P450 in human brain: implication in disease pathogenesis. J of Neural Transmission Supplementa 70: 167-171.
8. Fukasawa T, Suzuki A, Otani K (2007) Effects of genetic polymorphism of cytochrome P450 enzymes on the pharmacokinetics of benzodiazepines. J Clin Pharm Ther 4: 333-341.
9. Guengerich FP (1999) Cytochrome P-450 3A4: regulation and role in drug metabolism. Annu Rev Pharmacol Toxicol 39: 1-17.
10. Gellner K, Eiselt R, Hustert E, Arnold H, Koch I, et al. (2001) Genomic organization of the human CYP3A locus: identification of a new, inducible CYP3A gene. Pharmacogenetics 11: 111-121.
11. Ozhemir V, Kalow W, Tang BK, Paterson AD, Walker SE, et al. (2000) Evaluation of the genetic component of variability in CYP3A4 activity: A repeated drug administration (RDA) method. Pharmacogenetics 5: 373-388.
12. Hsu MH, Savas U, Griffin KJ, Johnson EF (2007) Human cytochrome P450 family 4 enzymes: function, genetic variation and regulation. Drug Metab Rev 39: 515-538.
13. Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, et al. (2001) Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 27: 383-391.
14. Lamba JK, Lin YS, Schuetz EG, Thummel KE (2002) Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev 10: 1271-1294.
15. Schuetz JD, Kauma S, Guzelian PS (1993) Identification of fetal liver cytochrome CYP3A7 in human endometrium and placenta. J Clin Invest 2: 1018-1024.
16. Domanski TL, Finta C, Halpert JR, Zaphiropoulos PG (2001) cDNA cloning and initial characterization or CYP3A43, a novel human cytochrome P450. Mol Pharmacol 59: 386-392.
17. Westlind A, Malmebo S, Johansson I, Otter C, Andersson TB, et al. (2001) Cloning and tissue distribution of a novel cytochrome P450 of the CYP3A subfamily, CYP3A43. Biochem Biophys Res Commun 281: 1349-1355.
18. Wennerholm A, Allqvist A, Svensson JO, Gustafsson LL, Mirghani RA, et al. (2005) Alprazolam as a probe for CYP3A using a single blood sample: pharmacokinetics of parent drug and of α- and 4-hydroxy metabolites in healthy subjects. Eur J Clin Pharmacol 61: 113-118.
19. Sethy VH, Harris DW (1982) Determination of biological activity of alprazolam, triazolam and their metabolite. J Pharm Pharmacol 34: 115-116.
20. Greenblatt DJ, Wright CE (1993) Clinical pharmacokinetics of alprazolam. Therapeutic implications. Clin Pharmacokinet 24: 453-471.
21. Hirota N, Ito K, Iwatsubo K, Green CE, Tyson CA, et al. (2001) In Vitro/ In Vivo Scaling or Alprazolam Metabolism by CYP3A4 and CYP3A5 in Humans. Biopharm Drug Dispos 22: 53-71.
22. Park JY, Kim KA, Shin JG (2006) CYP3A5 polymorphism and alprazolam pharmacokinetics/pharmacodynamics. Clin Pharm Ther 6: 715-720.
23. Park JY, Kim KA, Park PW, Lee OJ, Kang DK, et al. (2006) Effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of alprazolam in healthy subjects. J Clin Pharm Ther 79: 590-599.
24. Chinta SJ, Pai HV, Upadhya SC, Boyd MR, Ravindranath V (2002) Constitutive expression and localization of the major drug metabolizing enzyme, cytochrome P4502D in human brain. Brain Res Mol Brain Res 103: 49-61.
25. Chomezynski P (1993) A reagent for the single step simultaneous isolation of RNA, DNA and protein from cell and tissue samples. Biotechniques 15: 532-537.
26. Williams ET, Leyk M, Wrighton SA, Davies PJ, Loose DS, et al. (2004) Estrogen regulation or the cytochrome P450 3A subfamily in humans. J Pharmacol Exp Ther 311: 728-735.
27. Kevil CG, Walsh L, Laroux S, Kalogeris T, Grisham MB, et al. (1997) An improved, rapid northern protocol. Biochem Biophys Res Commun 238: 277-279.