Research Progress in Toxic Effects of Antitumor Drugs Mediated by Drug Metabolism Enzymes and Isoforms
ZHENG Jin-qi1,2, WANG Qian1, YANG Xi1, LOU Yan1*, ZENG Su3
1. The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000,China; 2. Zhejiang Institute for Food and Drug Control, Hangzhou 310052,China; 3. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
Abstract��Antitumor drugs have the characteristics of low therapeutic index, narrow safety window, and so on, which are prone to have toxic and side effects in the course of clinical therapy, thus limiting their use. In recent years, some studies have pointed out that the mechanism of adverse reactions of antitumor drugs is related to drug metabolism enzymes, receptors and transporters. Among them, drug metabolism enzymes and their gene polymorphisms play an important role in the toxic and side effects of antitumor drugs. In this paper, we analyze and summarize the side effects of antitumor drugs mediated by drug metabolism enzymes, mainly from the aspects of the roles of metabolic enzymes and their gene polymorphism in the metabolic activation and metabolic detoxification of antitumor drugs, in order to effectively avoid or reduce the toxic side effects of antitumor drugs, and to provide a reference for individualized treatment of cancer.
֣����,��ǰ,��ϣ,¥��,����. ҩ���лø�������ͽ鵼�Ŀ�����ҩ���ٴ����Է�Ӧ�о���չ[J]. �й�ҩѧ��־, 2017, 52(13): 1115-1119.
ZHENG Jin-qi, WANG Qian, YANG Xi, LOU Yan, ZENG Su. Research Progress in Toxic Effects of Antitumor Drugs Mediated by Drug Metabolism Enzymes and Isoforms. Chinese Pharmaceutical Journal, 2017, 52(13): 1115-1119.
ZANGER U M, SCHWAB M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther, 2013, 138(1): 103-141.
[2]
SCRIPTURE C D, FIGG W D. Drug interactions in cancer therapy. Nat Rev Cancer, 2006, 6(7): 546-558.
[3]
VAN LEEUWEN R W F, VAN GELDER T, MATHIJSSEN R H J, et al. Drug-drug interactions with tyrosine-kinase inhibitors: a clinical perspective. Lancet Onco, 2014, 15(8): e315-e326.
[4]
VAN LEEUWEN R W F, BRUNDEL D H S, NEEF C, et al. Prevalence of potential drug-drug interactions in cancer patients treated with oral anticancer drugs. Br J Cancer, 2013, 108(5): 1071-1078.
[5]
SIM S C, KACEVSKA M, INGELMAN-SUNDBERG M. Pharmacogenomics of drug-metabolizing enzymes: a recent update on clinical implications and endogenous effects. Pharmacogenomics J, 2013, 13(1): 1-11.
[6]
KITAMURA Y, MORIGUCHI M, KANEKO H, et al. Determination of probability distribution of diplotype configuration(diplotype distribution) for each subject from genotypic data using the EM algorithm. Ann Hum Genet, 2002, 66(3):183-193.
[7]
PREISSNER S C, HOFFMANN M F, PREISSNER R, et al. Polymorphic cytochrome P450 enzymes(CYPs) and their role in personalized therapy. PLoS One, 2013, 8(12): 1611-1614.
[8]
LU F, ZAHID M, WANG C, et al. Resveratrol prevents estrogen-DNA adduct formation and neoplastic transformation in MCF-10F cells. Cancer Prev Res(Phila), 2008,1(2): 135-145.
[9]
CHOI H, CHUN Y S, SHIN Y J, et al. Curcumin attenuates cytochrome P450 induction in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin by ROS-dependently degrading AhR and ARNT. Cancer Sci, 2008, 99(12): 2518-2524. WILLSON T M, KLIEWER S A. PXR, CAR and drug metabolism. Nat Rev Drug Discov, 2002, 1(4): 259-266. KRETSCHMER X C, BALDWIN W S. CAR and PXR: xenosensors of endocrine disrupters?. Chem Biol Interact, 2005, 155(3): 111-128. TOLSON A H, WANG H. Regulation of drug-metabolizing enzymes by xenobiotic receptors: PXR and CAR. Adv Drug Deliv Rev, 2010, 62(13): 1238-1249. JONES S A, MOORE L B, SHENK J L, et al. The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution. Mol Endocrinol, 2000, 14(1): 27-39. LIU H, LOU G, LI C, et al. HBx Inhibits CYP2E1 gene expression via downregulating HNF4a in human hepatoma cells. PLoS One, 2014, 9(9): e107913. DE FABIANI E, MITRO N, ANZULOVICH A C, et al. The negative effects of bile acids and tumor necrosis factor-alpha on the transcription of cholesterol 7alpha-hydroxylase gene(CYP7A1) converge to hepatic nuclear factor-4: a novel mechanism of feedback regulation of bile acid synthesis mediated by nuclear receptors. J Biol Chem, 2001, 276(33):30708-30716. CHEN T C L, SAKAKI T, YAMAMOTO K, et al. The roles of cytochrome P450 enzymes in prostate cancer development and treatment. Anticancer Res, 2012, 32(1):291-298. BARTIK L, WHITFIELD G K, KACZMARSKA M, et al. Curcumin: a novel nutritionally derived ligand of the vitamin D receptor with implications for colon cancer chemoprevention . J Nutr Biochem, 2010, 21(12):1153-1161. KALTHOFF S, WINKLER A, FREIBERG N, et al. Gender matters: estrogen receptor alpha(ER��) and histone deacetylase(HDAC) 1 and 2 control the gender-specific transcriptional regulation of human uridine diphosphate glucuronosyltransferases genes(UGT1A). J Hepatol, 2013, 59(4):797-804. KUO L C, CHENG L C, LIN C J, et al. Dioxin and estrogen signaling in lung adenocarcinoma cells with different aryl hydrocarbon receptor/estrogen receptor �� phenotypes. Am J Respir Cell Mol Biol, 2013, 49(6):1064-1073. MOHDSIDDIQUE M U, MCCANN G J, SONAWANE V R, et al. Quinazoline derivatives as selective CYP1B1 inhibitorss. Eur J Med Chem, 2017, 16(130):320-327. FAN Z, WANG Z, CHEN W, et al. Association between the CYP11 family and six cancer types. Oncol Lett, 2016, 12(1):35-40. DP��QUET S, FAZLI L, GROSSE L, et al. Differential expression of the androgen-conjugating UGT2B15 and UGT2B17 enzymes in prostate tumor cells during cancer progression. J Clin Endocrinol Metab, 2012, 97(3):428-432. OKAMOTO T, MOMOSE S, HINO O. Suppression of cytochrome P450 1A1 and 4A1 gene expression in renal carcinomas of TSC2 gene mutant(Eker) rats. Int J Oncol, 2001, 18(1):147-149. MARGAILLAN G, ROULEAU M, FALLON J K, et al. Quantitative profiling of human renal UDP-glucuronosyltransferases and glucuronidation activity: a comparison of normal and tumoral kidney tissues. Drug Metab Dispos, 2015, 43(4):611-619. LIU Y. Genetic polymorphism and mRNA levels of CYP450IIE1 and GSTP1 in alcoholic liver disease. Changchun:Jilin Univ, 2009. XIE S, LI C Y, NIU Y L. Drug metabolism enzymes and liver cancer. Shandong Med J(ɽ��ҽҩ),2010,50(5):113-114. YANG X, HUTTER M, GOH W W, et al. CYP4Z1-A Human cytochrome P450 enzyme that might hold the key to curing breast cancer. Curr Pharm Des, 2017,23(1):1-5. HE X, FENG S. Role of metabolic enzymes P450(CYP) on activating procarcinogen and their polymorphisms on the risk of cancers. Curr Drug Metab, 2015, 16(10):850-863. SCHMELZLE M, DIZDAR L, MATTHAEI H, et al. Esophageal cancer proliferation is mediated by cytochrome P450 2C9(CYP2C9). Prostaglandins Other Lipid Mediat, 2011, 94(1-2):25-33. DURA P, SALOMON J, TE MORSCHE R H, et al. High enzyme activity UGT1A1 or low activity UGT1A8 and UGT2B4 genotypes increase esophageal cancer risk. Int J Oncol, 2012, 40(6):1789-1796. ZHOU S Y, HU J A, HUANG C. DNA methylation of oxidative metabolic enzymes:research progres. Chin J Pharmacol Toxic(�й�ҩ��ѧ�붾��ѧ��־),2016,30(4):405-411. YANG Z Z, YU Q Q, YU L S, et al. Development of research on regulation mechanism of epigenetic modifications for drug metabolic enzymes. Chin Pharm J(�й�ҩѧ��־), 2013, 48(17): 1425-1428. ZHANG L, ZHANG G L. Research progress in epigenetic regulation of cytochrome P450 genes encoding drug metabolizing enzymes. Prog Phy Sci(�����ѧ��չ),2010, 41(3):209-213. MACALLISTER S L, MARTIN-BRISAC N, LAU V, et al. Acrolein and chloroacetaldehyde: an examination of the cell and cell-free biomarkers of toxicity. Chem Biol Interact, 2013, 202(1-3): 259-266. LI F, PATTERSON A D, H��FER C C, et al. Comparative metabolism of cyclophosphamide and ifosfamide in the mouse using UPLC-ESI-QTOFMS-based metabolomics. Biochem Pharmacol, 2010, 80(7): 1063-1074. CHINNASWAMY G, ERRINGTON J, FOOT A, et al. Pharmacokinetics of cyclophosphamide and its metabolites in paediatric patients receiving high-dose myeloablative therapy. Eur J Cancer, 2011, 47(10): 1556-1563. PASS G J, CARRIE D, BOYLAN M, et al. Role of hepatic cytochrome p450s in the pharmacokinetics and toxicity of cyclophosphamide: studies with the hepatic cytochrome p450 reductase null mouse. Cancer Res, 2005, 65(10): 4211-4217. LIEHR J G, ROCCI M J. 4-Hydroxylation of estrogens as marker of human mammary tumors. Proc Natl Acad Sci, 1996, 93(8):3294-3296. MCFAYDEN M C, MCLEOD H L, JACKSON F C, et al. Cytochrome P450 CYP1B1 protein expression: a novel mechanism of anticancer drug resistance. Biochem Pharmacol, 2001, 62(2):207-212. BOURNIQUE B, LEMARI�� A. Docetaxel(Taxotere) is not metabolized by recombinant human CYP1B1 in vitro, but acts as an effector of this isozyme. Drug Metab Dispos, 2002, 30(11):1149-1152. RIZZO R, SPAGGIARI F, INDELLI M, et al. Association of CYP1B1 with hypersensitivity induced by taxane therapy in breast cancer patients. Breast Cancer Res Treat, 2010, 124(2):593-598. MARSH S, PAUL J, KING C R, et al. Pharmacogenetic assessment of toxicity and outcome after platinum plus taxane chemotherapy in ovarian cancer: the scottish randomised trial in ovarian cancer. J Clin Oncol, 2007, 25(29):4528-4535. BAKER S D, VERWEIJ J, CUSATIS G A. Pharmacogenetic pathwayanalysis of docetaxel elimination . Clin Pharmacol Ther, 2009, 85(2): 155-163. TSAI S M, LIN C Y, WU S H, et al. Side effects after docetaxel treatment in Taiwanese breast cancer patients with CYP3A4, CYP3A5, and ABCB1 gene polymorphisms . Clin Chim Acta, 2009, 404(2): 160-165. LEWIS L D, MILLER A A, ROSNER G L, et al. A comparison of the pharmacokinetics and pharmacodynamics of docetaxel between African-American and Caucasian cancer patients: CALGB 9871 . Clin Cancer Res, 2007, 13(11): 3302-3311. PASTINA I, GIOVANNETTI E, CHIONI A, et al. Cytochrome 450 1B1( CYP1B1) polymorphisms associated with response to docetaxel in Castration-Resistant Prostate Cancer( CRPC) patients. BMC Cancer, 2010, 10: 511. doi:10.1186/1471-2407-10-511. VASILE E, TIBALDI C, LEON G L, et al. Cytochrome P450 1B1( CYP1B1) polymorphisms are associated with clinical outcome of docetaxel in non-small cell lung cancer(NSCLC) patients. J Cancer Res Clin Oncol, 2015, 141(7): 1189-1194. BERGMANN T K, BRASCH-ANDERSEN C, GR��EN H, et al. Impact of CYP2C8* 3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer. Pharmacogenomics J, 2011, 11(2): 113-120. LEE K W, CHAN S L. Hepatotoxicity of targeted therapy for cancer. Expert Opin Drug Metab Toxicol, 2016, 12(7):789-802. BARBARA J E, KAZMI F, PARKINSON A, et al. Metabolism-dependent inhibition of CYP3A4 by lapatinib: evidence for formation of a metabolic intermediate complex with a nitroso/oxime metabolite formed via a nitrone intermediate. Drug Metab Dispos, 2013, 41(5):1012-1022. HARDY K D, WAHLIN M D, PAPAGEORGIOU I, et al. Studies on the role of metabolic activation in tyrosine kinase inhibitor-dependent hepatotoxicity: induction of CYP3A4 enhances the cytotoxicity of lapatinib in HepaRG cells. Drug Metab Dispos, 2014, 42(1):162-171. FURET Y,BECHTEI Y,LE G C, et al. Clinical relevance of N-acetyltransferase type 2(NAT2)genetic polymorphism. Th��rapie, 2002,57(5): 427-431. SAITO Y, SAI K, MAEKAWA K, et al. Close association of UGT1A9 IVS1+399C>T with UGT1A1*28, *6, or *60 haplotype and its apparent influence on 7-ethyl-10-hydroxycamptothecin(SN-38) glucuronidation in Japanese. Drug Metab Dispos, 2009, 37(2): 272-276. COTE J F, KIRZIN S, KRAMAR A, et al. UGT1A1 polymorphism can predict hematologic toxicity in patients treated with irinotecan. Clin Cancer Res, 2007, 13(11): 3269-3275. PETERS U, PREISLER-ADAMS S, HEBEISEN A, et al. Glutathione S-transferase genetic polymorphisms and individual sensitivity to the ototoxic effect of cisplatin. Anticancer Drugs, 2000, 11(8):639-643. MARSH S, HOSKINS J M. Irinotecan pharmacogenomics. Pharmacogenomics, 2010, 11(7): 1003-1010. BAKER S D,DIASIO R B,O��REILLY S,et al.Phase I and pharmacologic study of oral 5-fluorouracil on a chronic daily schedule in combination with the dihydropyrimidine dehydrogenase inactivator eniluracil.J Clin Oncol,2000,18(4):915-926. LEE N H. Pharmacogenetics of drug metabolizing enzymes and transporters: effects on pharmacokinetics and pharmacodynamics of anticancer agents. Anticancer Agents Med Chem, 2010, 10(8): 583-592. PAPANASTASOPOULOS P, STEBBING J. Molecular basis of 5-fluorouracil-related toxicity: lessons from clinical practice. Anticancer Res, 2014, 34(4): 1531-1536. MOREL A, BOISDRON-CELLE M, FEY L, et al. Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance. Mol Cancer Ther, 2006, 5(11): 2895-2904. LIU J T, JIAO Y Y, ZHANG Y H. Pharmacogenomics on anti-cancer drugs: research advances. J Inter Pharm Res(����ҩѧ�о���־),2014, 41(1):51-56. BOSCH T M. Pharmacogenomics of drug-metabolizing enzymes and drug transporters in chemotherapy. Methods Mol Biol, 2008, 448: 63-76. INNOCENTI F,LYER L,RATAIN M J.Pharmacogenetics:a tool for individualizing antineoplastic therapy.Clin Pharmacokinet,2000,39(5): 315-325. HSYU P H, PIGNATARO D S, MATSCHKE K. Effect of aprepitant, a moderate CYP3A4 inhibitor, on bosutinib exposure in healthy subjects. Eur J Clin Pharmacol, 2017, 73(1):49-56. SONG X, VARKER H, EICHELBAUM M, et al. Treatment of lung cancer patients and concomitant use of drugs interacting with cytochrome P450 isoenzymes. Lung Cancer, 2011, 74(1):103-111.
2017, Vol. 52 
