Back
 PP  Vol.4 No.2 , April 2013
Xenobiotic-Metabolizing Enzymes in Skeletal Muscle of Children and Adolescents
Dora Molina-Ortiz, José Francisco González-Zamora, Rafael Camacho-Carranza, Ocarol Lopez-Acosta, Oscar Colin-Martinez, Adriana Miriam Domínguez-Ramírez, Araceli Vences-Mejía
Show more
Abstract: Cytochrome P450 (CYP) enzymes metabolize endogenous compounds such as steroid hormones, fatty acids, and xenobiotics, including drugs and carcinogens. The skeletal muscle is highly exposed to circulating xenobiotics; nevertheless the knowledge on the expression of these enzymes not only in adult skeletal muscle but also in younger individuals has been very little. Therefore, the aim of the present study was to investigate the expression of CYP enzymes in healthy skeletal muscles of children and adolescents. This was investigated in a total of 18 biopsies taken from the quadriceps skeletal muscle of younger patients: 9 boys and 9 girls (≤18 years) by using specific antibodies in immunoblots and by RT-PCR mRNA analysis. The mRNA transcripts for CYP1B1 and CYP2E1 were consistently detected in all samples, but in the immunoblot only was identified CYP1B1 protein in four samples. Regarding CYP1A1, CYP3A4 and CYP3A5 enzymes in skeletal muscle, there were found in some samples in both techniques, although with significant inter-individual variations. Finally CYP2W1 only was detected in one sample belonging to the youngest patient. These data show that a range of CYP enzymes are expressed in the skeletal muscle of children and adolescents, suggesting that the metabolism of several xenobiotic chemicals to which humans are exposed takes place in muscle cells. Moreover, since the potential participation of muscles is a fact in pharmacokinetics of many therapeutic drugs, expression of CYPs in skeletal muscle may play an important role in drug-dependent toxicity.
Keywords: Cytochrome P450; Skeletal Muscle; Children; Adolescents
Cite this paper: D. Molina-Ortiz, J. González-Zamora, R. Camacho-Carranza, O. Lopez-Acosta, O. Colin-Martinez, A. Domínguez-Ramírez and A. Vences-Mejía, "Xenobiotic-Metabolizing Enzymes in Skeletal Muscle of Children and Adolescents," Pharmacology & Pharmacy, Vol. 4 No. 2, 2013, pp. 231-239. doi: 10.4236/pp.2013.42032.
References

[1]   J. Owczarek, M. Jasińska and D. Orszulak-Michalak, “Drug-Induced Myopathies. An Overview of the Possible Mechanisms,” Pharmacology, Vol. 57, No. 1, 2005, pp. 23-34.

[2]   T. Khazaeinia, A. A. Ramsey and Y. K. Tam, “The Effects of Exercise on the Pharmacokinetics of Drugs,” Journal of Pharmacy and Pharmaceutical Sciences, Vol. 3, No. 3, 2000, pp. 292-302.

[3]   J. R. Herman, “Drug Interaction and Statins,” Canadian Medical Association Journal, Vol. 161, 1999, pp. 2811286.

[4]   J. Warren, P. Blumbergs and P. Thompson, “Rhabdomyolysis: A Review,” Muscle & Nerve, Vol. 25, No. 3, 2002, pp. 332-347. doi:10.1002/mus.10053

[5]   Z. Argov, “Drug-Induced Myopathies,” Current Opinion in Neurology, Vol. 13, No. 5, 2000, pp. 541-545. doi:10.1097/00019052-200010000-00006

[6]   D. Nebert and T. Dalton, “The Role of Cytochrome P450 Enzymes in Endogenous Signalling Pathways and Envi ronmental Carcinogenesis,” Nature Reviews Cancer, Vol. 6, 2006, pp. 947-960. doi:10.1038/nrc2015

[7]   B. Park, M. Pirmohamed and N. Kitteringham, “The Role of Cytochrome P450 Enzymes in Hepatic and Extrahepatic Human Drug Toxicity,” Pharmacology & Therapeutics, Vol. 68, No. 3, 1995, pp. 385-424. doi:10.1016/0163-7258(95)02013-6

[8]   I. Biéche, C. Narjoz, T. Asselah, S. Vacher, P. Marcellin, R. Lidereau, P. Beaune and E. de Waziers, “Reverse Transcriptase-PCR Quantification of mRNA Levels from Cytochrome (CYP)1, CYP2 and CYP3 Families in 22 Different Human Tissues,” Pharmacogenetics & Genomics, Vol. 17, No. 9, 2007, pp. 731-742. doi:10.1097/FPC.0b013e32810f2e58

[9]   P. Pavek and Z. Dvora, “Xenobiotic-Induced Transcriptional Regulation of Xenobiotic Metabolizing Enzymes of the Cytochrome P450 Superfamily in Human Extrahepatic Tissues,” Current Drug Metabolism, Vol. 9, No. 2, 2008, pp. 129-143. doi:10.2174/138920008783571774

[10]   S. Ellero, G. Chakhtoura, C. Barreau, S. Langoue, C. H. Benelli, L. Penicaud, P. Beaune and I. de Waziers, “Xenobiotic-Metabolizing Cytochromes P450 in Human White Adipose Tissue: Expression and Induction,” Drug Metabolism and Disposition, Vol. 38, No. 4, 2010, pp. 679-686. doi:10.1124/dmd.109.029249

[11]   S. C. Dogra, M. L. Whitelaw and B. K. May, “Transcriptional Activation of Cytochrome P450 Genes by Different Classes of Chemical Inducers,” Clinical and Experimental Pharmacology and Physiology, Vol. 25, No. 1, 1998, pp. 1-9. doi:10.1111/j.1440-1681.1998.tb02135.x

[12]   I. Bergheim, C. Bode and A. Parlesak, “Distribution of Cytochrome P450 2C, 2E1, 3A4, and 3A5 in Human Colon Mucosa,” BMC Clinical Pharmacology, Vol. 5, 2005, p. 4.

[13]   C. Tang, J. H. Lin and A. Y. Lu, “Metabolism-Based Drug-Drug Interactions: What Determines Individual Variability in Cytochrome P450 Induction?” Drug Metabolism and Disposition, Vol. 33, No. 5, 2005, pp. 603613. doi:10.1124/dmd.104.003236

[14]   X. Ding and L. Kaqminski, “Human Extrahepatic Cytochrome P450: Function in Xenobiotic Metabolism and Tissue-Selective Chemical Toxicity in the Respiratory and Gastrointestinal Tracts,” Annual Review of Pharmacology and Toxicology, Vol. 43, 2003, pp. 149-173. doi:10.1146/annurev.pharmtox.43.100901.140251

[15]   P. Rickham, “Human Experimentation. Code of Ethics of the World Medical Association,” British Medical Journal, Vol. 2, 1964, p. 177. doi:10.1136/bmj.2.5402.177

[16]   O. Lowry, N. Rosebrough, A. Farr and R. Randall, “Protein Measurement with the Folin Phonol Reagent,” The Journal of Biological Chemistry, Vol. 193, No. 1, 1951, pp. 265-275.

[17]   K. Livack and T. Schmittgen, “Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2 Delta Delta C (T),” Methods, Vol. 25, 2001, pp. 402-408.

[18]   G. L. Kearns, S. M. Abdel-Rahman, S. W. Alander, D. L. Blowey, J. S. Leeder, et al., “Developmental Pharmacology—Drug Disposition, Action, and Therapy in Infants and Children,” The New England Journal of Medicine, Vol. 349, 2003, pp. 1157-1167. doi:10.1056/NEJMra035092

[19]   D. Nebert, T. Dalton, A. Okey and F. Gonzalez, “Role of Aryl Hydrocarbon Receptor-Mediated Induction of the CYP1 Enzymes in Environmental Toxicity and Cancer,” The Journal of Biological Chemistry, Vol. 279, 2004, pp. 23847-23850. doi:10.1074/jbc.R400004200

[20]   D. Nebert and C. Karp, “Endogenous Functions of the Aryl Hydrocarbon Receptor (AHR): Intersection of Cytochrome P450 1 (CYP1)-Metabolized Eicosanoids and AHR Biology,” The Journal of Biological Chemistry, Vol. 283, 2008, pp. 36061-36065. doi:10.1074/jbc.R800053200

[21]   L. Nguyen and C. Bradfield, “The Search for Endogenous Activators of the Aryl Hydrocarbon Receptor,” Chemical Research in Toxicology, Vol. 21, No. 1, 2008, pp. 102116. doi:10.1021/tx7001965

[22]   T. Shimada, “Arylhydrocarbon Receptor-Dependent Induction of Liver and Lung Cytochromes P450 1A1, 1A2, and 1B1 by Polycyclic Aromatic Hydrocarbons and Polychlorinated Biphenyls in Genetically Engineered C57BL/6J Mice,” Carcinogenesis, Vol. 23, No. 7, 2002, pp. 1199-1207. doi:10.1093/carcin/23.7.1199

[23]   C. Martucci and J. Fishman, “P450 Enzymes of Estrogen Metabolism,” Pharmacology & Therapeutics, Vol. 57, No. 2-3, 1993, pp. 237-257. doi:10.1016/0163-7258(93)90057-K

[24]   K. Aizawa, M. Iemitsu, T. Otsuki, S. Maeda, T. Miyauchi and N. Mesaki, “Sex Differences in Steroidogenesis in Skeletal Muscle Following a Single Bout of Exercise in Rats,” Journal of Applied Physiology, Vol. 104, No. 1, 2008, pp. 67-74. doi:10.1152/japplphysiol.00558.2007

[25]   C. Patten, P. Thomas, R. Guy, M. Lee, F. Gonzalez, F. Guengerich, et al., “Cytochrome P450 Enzymes Involved in Acetaminophen Activation by Rat and Human Liver Microsomes and Their Kinetics,” Chemical Research in Toxicology, Vol. 6, No. 4, 1993, pp. 511-518. doi:10.1021/tx00034a019

[26]   J. Raucy, J. Lasker, C. Lieber and M. Black, “Acetaminophen Activation by Human Liver Cytochromes P450IIE1 and P450IA2,” Archives of Biochemistry and Biophysics, Vol. 271, No. 1, 1989, pp. 270-283. doi:10.1016/0003-9861(89)90278-6

[27]   M. Iwanari, M. Nakajima, R. Kizu, K. Hayakawa and T. Yokoi, “Induction of CYP1A1, CYP1A2, and CYP1B1 mRNAs by Nitropolycyclic Aromatic Hydrocarbons in Various Human Tissue-Derived Cells: Chemical-, Cytochrome P450 Isoform-, and Cell-Specific Differences,” Archives of Toxicology, Vol. 76, No. 5-6, 2002, pp. 287-298. doi:10.1007/s00204-002-0340-z

[28]   A. Gomez, M. Karlgren, D. Edler, M. Bernal, S. Mkrtchian, et al., “Expression of CYP2W1 in Colon Tumors: Regulation by Gene Methylation,” Pharmacogenomics, Vol. 8, No. 10, 2007, pp. 1315-1325. doi:10.2217/14622416.8.10.1315

[29]   J. Riggs, “Alcohol-Associated Rhabdomyolysis: Ethanol Induction of Cytochrome P450 May Potentiate Myotoxicity,” Clinical Neuropharmacology, Vol. 21, No. 6, 1998, pp. 363-364.

[30]   C. Lieber, “Cytochrome P-4502E1: Its Physiological and Pathological Role,” Physiological Reviews, Vol. 77, No. 2, 1997, pp. 517-544.

[31]   M. J. J. Ronis, K. O. Lindros and M. Ingelman-Sundberg, “The CYP2E Subfamily,” In: C. Ioannides and D. V. Parke, Eds., Cytochromes P450: Metabolic and Toxicological Aspects, CRC Press, Boca Raton, 1996, pp. 211239.

[32]   D. R. Nelson, “Cytochrome P450 and the Individuality of Species,” Archives of Biochemistry and Biophysics, Vol. 369, No. 1, 1999, pp. 1-10. doi:10.1006/abbi.1999.1352

[33]   V. Wacher, C. Wu and L. Benet, “Overlapping Substrate Specificities and Tissue Distribution of Cytochrome P450 3A and P-Glycoprotein: Implications for Drug Delivery and Activity in Cancer Chemotherapy,” Oncology & Radiotherapy, Vol. 13, No. 3, 1995, pp. 129-134. doi:10.1002/mc.2940130302

[34]   P. Guengerich, “Cytochrome P450 3A4: Regulation and Role in Drug Metabolism,” Annual Review of Pharmacology and Toxicology, Vol. 39, 1999, pp. 1-17. doi:10.1146/annurev.pharmtox.39.1.1

[35]   K. Thummel, D. Shen, T. Podoll, K. Kunze, W. Trager, et al., “Use of Midazolam as a Human Cytochrome P450 3A Probe: II. Characterization of Interand Intraindividual Hepatic CYP3A Variability after Liver Transplantation,” Journal of Pharmacology and Experimental Therapeutics, Vol. 271, No. 1, 1994, pp. 557-566.

[36]   L. M. Forrester, C. J. Henderson, M. J.Glancey, D. J. Back, B. K. Park, S. E. Ball, N. R. Kitteringham, A. W. McLaren, J. S. Miles, P. Skett, et al., “Relative Expression of Cytochrome P450 Isoenzymes in Human Liver and Association with the Metabolism of Drugs and Xenobiotics,” Biochemical Journal, Vol. 281, 1992, pp. 359-368.

 
 
Top