Advertisement

BioMetals

, Volume 29, Issue 1, pp 107–118 | Cite as

Exceptions in patterns of arsenic compounds in urine of acute promyelocytic leukaemia patients treated with As2O3

  • Zdenka Šlejkovec
  • Helena Podgornik
  • Peter Černelč
  • Ingrid Falnoga
Article

Abstract

Arsenic trioxide (As(III) in solution) has been shown to be the most active single agent in combating acute promyelocytic leukemia (APL). It is metabolized and excreted via urine as monomethylarsonic acid (MMA), dimethylarsinic acid (DMA) and As(V), along with excess As(III). In our study eight APL patients were treated (intravenously) with 0.15 mg As2O3/kg/day. During the therapy As(III) and its metabolites were followed in pre- and post-infusion urine using HPLC for separation followed by on-line detection using hydride generation-atomic fluorescence spectrometry. Five patients had a normal excretion pattern of residual arsenic compounds in morning pre-infusion urine, with 15–25 % of As(III), 35–55 % of DMA, 25–30 % of MMA and 1–5 % of As(V), while three patients showed unexpected exceptions from typical excretion patterns of arsenic compounds (i) a high DMA/MMA ratio (factor 5.3), (ii) severe As(III) oxidation (10.2 % As(III) converted to As(V)) or (iii) the presence of an excessive amount of As(III) (average 30.4 % of total arsenic). Intriguing was the occurrence of post-infusion oxidation of As(III) to As(V) observed in almost all patients and being especially high (>40 %) in patient with increased residual As(V). Results indicate that arsenic metabolites patterns can be unpredictable. Observed high levels of un-metabolised As(III) are a warning signal for side effects and for routine determination of arsenic metabolites during first days of treatment. High or low percentages of MMA or DMA did not show any observable effect on treatment results, while clear presence of post-infusion As(V) supports theoretical claims of in vivo oxidation (detoxification) of As(III) to As(V) associated with various metabolic processes.

Keywords

Arsenic trioxide Acute promyelocytic leukemia Metabolites Urine Speciation Biotransformation 

Notes

Acknowledgments

The authors express sincere gratitude to Dr. Reberšek, Ivana Nerad and nurses at Haematology Department of University Medical Centre Ljubljana for collection of urine samples and to Dr. Darja Mazej for ICP-MS analysis of total arsenic. This study was in part supported by Slovenian Research Agency through J3-0161 and J3-6104 research Projects and EU project HEELS and CHROME.

References

  1. Aposhian HV, Aposhian MM (2006) Arsenic toxicology: five questions. Chem Res Toxicol 19:1–15CrossRefPubMedGoogle Scholar
  2. Aposhian HV, Zakharyan RA, Avram MD, Kopplin MJ, Wollenberg ML (2003) Oxidation and detoxification of trivalent arsenic species. Toxicol Appl Pharmacol 193:1–9CrossRefPubMedGoogle Scholar
  3. Bu N, Wang HY, Hao WH, Liu X, Xu S, Wu B, Anan Y, Ogra Y, Lou YJ, Naranmandura H (2011) Generation of thioarsenicals is dependent on the enterohepatic circulation in rats. Metallomics 3:1064–1073CrossRefPubMedGoogle Scholar
  4. Cullen WR (2014) Chemical mechanism of arsenic biomethylation. Chem Res Toxicol 21:457–461CrossRefGoogle Scholar
  5. Das AK, Chakraborty R, Cervera ML, De la Guardia M (1996) Metal speciation in biological fluids—a review. Mikrochim Acta 122:209–246CrossRefGoogle Scholar
  6. DelRazo LM, García-Vargas GG, Vargas H, Albores A, Gonsebatt ME, Montero R, Ostrosky Wegman P, Kelsh M, Cebrian ME (1997) Altered profile of urinary arsenic metabolites in adults with chronic arsenicism. A pilot study. Arch Toxicol 71:211–217CrossRefGoogle Scholar
  7. Douer D, Tallman MS (2005) Arsenic trioxide: new clinical experience with an old medication in hematologic malignancies. J Clin Oncol 23:2396–2410CrossRefPubMedGoogle Scholar
  8. El-Masri HA, Kenyon EM (2008) Development of a human physiologically based pharmacokinetic (PBPK) model for inorganic arsenic and its momo- and di-methylated metabolites. J Pharmacokinet Pharmcodyn 35:31–68CrossRefGoogle Scholar
  9. Engström K, Vahter M, Jurkovic Mlakar S, Concha G, Nermell B, Raqib R, Cardozo A, Broberg K (2011) Polymorphisms in arsenic(+III oxidation state) methyltransferase (AS3MT) predict gene expression of AS3MT as well as arsenic metabolism. Environ Health Persp 119:182–188CrossRefGoogle Scholar
  10. Feldmann J, Lai VWM, Cullen WR, Ma MS, Lu XF, Le XC (1999) Sample preparation and storage can change arsenic speciation in human urine. Clin Chem 45:1988–1997PubMedGoogle Scholar
  11. Fujisawa S, Ohno R, Shigeno K, Sahara N, Nakamura S, Naito K, Kobayashi M, Shinjo K, Takeshita A, Suzuki Y, Hashimoto H, Kinoshita K, Shimoya M, Kaise T, Ohnishi K (2007) Pharmacokinetics of arsenic species in Japanese patients with relapsed or refractory acute promyelocytic leukemia treated with arsenic trioxide. Cancer Chemother Pharmacol 59:485–493CrossRefPubMedGoogle Scholar
  12. Fukai Y, Hirata M, Ueno M, Ichikawa N, Kobayashi H, Saitoh H, Sakurai T, Kinoshita K, Kaise T, Ohta S (2006) Clinical pharmacokinetic study of arsenic trioxide in an acute promyelocytic leukemia (APL) patient: speciation of arsenic metabolites in serum and urine. Biol Pharm Bull 29:1022–1027CrossRefPubMedGoogle Scholar
  13. Gong ZL, Lu XF, Cullen WR, Le XC (2001) Unstable trivalent arsenic metabolites, monomethylarsonous acid and dimethylarsinous acid. J Anal At Spectrom 16:1409–1413CrossRefGoogle Scholar
  14. Gribble MO, Crainiceanu CM, Howard BV, Umans JG, Francesconi KA, Goessler W, Zhang Y, Silbergeld EK, Guallar E, Navas-Acien A (2013) Body composition and arsenic metabolism: a cross-sectional analysis in the Strong Heart Study. Environ Health 12:107CrossRefPubMedCentralPubMedGoogle Scholar
  15. Harari F, Engström K, Concha G, Colque G, Vahter M, Broberg K (2013) N-6-adenine-specific DNA methyltransferase 1 (N6AMT1) polymorphisms and arsenic methylation in Andean women. Environ Health Perspect 121:797–803CrossRefPubMedCentralPubMedGoogle Scholar
  16. Heinrich-Ramm R, Shaller KH, Horn J, Angerer J (2003) Arsenic species excretion after dimercaptopropanesulfonic acid (DMPS) treatment of an acute arsenic trioxide poisoning. Arch Toxicol 77:63–68PubMedGoogle Scholar
  17. Hughes MF, Beck BD, Chen Y, Lewis AS, Thomas DJ (2011) Arsenic exposure and toxicology: a historical perspective. Toxicol Sci 123:305–332CrossRefPubMedCentralPubMedGoogle Scholar
  18. Iriyama N, Yuan B, Yoshino Y, Hatta Y, Horikoshi A, Aizawa S, Takeuchi J, Toyoda H (2013) Aquaporin 9, a promising predictor for the cytocidal effects of arsenic trioxide in acute promyelocytic leukemia cell lines and primary blasts. Oncol Rep 29:2362–2368PubMedGoogle Scholar
  19. Jing Y, Dai J, Chalmers-Redman RME, Tatton WG, Waxman S (1999) Arsenic trioxide selectively induces acute promyelocytic leukaemia cell apoptosis via a hydrogen peroxide-dependent pathway. Blood 94:2102–2111PubMedGoogle Scholar
  20. Mandal BK, Ogra Y, Suzuki KT (2001) Identification of dimethylarsinous and monomethylarsonous acids in human urine of the arsenic-affected areas in West Bengal, India. Chem Res Toxicol 14:371–378CrossRefPubMedGoogle Scholar
  21. Miller WH, Schipper HM, Lee JS, Singer J, Waxman S (2002) Mechanisms of action of arsenic trioxide. Cancer Res 62:3893–3903PubMedGoogle Scholar
  22. Rehman K, Naramandura H (2012) Arsenic methabolism and thioarsenicals. Metallomics 4:881–892CrossRefPubMedGoogle Scholar
  23. Rust DM, Soignet SL (2001) Risk/benefit profile of arsenic trioxide. Oncologist 6:29–32CrossRefPubMedGoogle Scholar
  24. Salvaggio A, Perito M, Miani L, Tavanelli M, Marzorati D (1991) Body mass index and liver enzyme activity in serum. Clin Chem 37(5):720–723PubMedGoogle Scholar
  25. Šlejkovec Z, Van Elteren JT (1999) Determination of arsenic compounds in reference materials by HPLC-UV-HG-AFS. Talanta 49:619–627CrossRefPubMedGoogle Scholar
  26. Šlejkovec Z, Falnoga I, Van Elteren JT, Goessler W, Raml R, Podgornik H, Černelč P (2008) Analytical artefacts in the speciation of arsenic in clinical samples. Anal Chim Acta 607:83–91CrossRefPubMedGoogle Scholar
  27. Soignet SL, Maslak P, Wang ZG, Jhanwar S, Calleja E, Dardashti LJ, Corso D, DeBlasio A, Gabrilove J, Scheinberg DA, Pandolfi PP, Warrell RP (1998) Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. New Engl J Med 339:1341–1348CrossRefPubMedGoogle Scholar
  28. Trisenox (2002) Product monograph. Cell Therapeutics Inc, LondonGoogle Scholar
  29. Vahter M (2002) Mechanisms of arsenic biotransformation. Toxicol 181:211–217CrossRefGoogle Scholar
  30. Vahter M, Concha G (2001) Role of metabolism in arsenic toxicity. Pharmacol Toxicol 89:1–5CrossRefPubMedGoogle Scholar
  31. Wang Z, Zhou J, Lu X, Gong Z, Le XC (2004) Arsenic speciation in urine from acute promyelocytic leukemia patients undergoing arsenic trioxide treatment. Chem Res Toxicol 17:95–103CrossRefPubMedGoogle Scholar
  32. Wang H, Xi S, Liu Z, Yang Y, Zheng Q, Wang F, Xu YY, Wang Y, Zheng Y, Sun GG (2011) Arsenic methylation metabolism and liver injury of acute promyelocytic leukemia patients undergoing arsenic trioxide treatment. Environ Toxicol 28:267–275CrossRefPubMedGoogle Scholar
  33. Watanabe T, Hirano S (2013) Metabolism of arsenic and its toxicological relevance. Arch Toxicol 87:969–979CrossRefPubMedGoogle Scholar
  34. Zhang Z, Chen Y, Meng HB, Sui MJ, Zhou Q, Shi C, Han LN, Wang H, Zhou J (2013) Determination of arsenic metabolites in patients with newly diagnosed acute promyelocytic leukemia treated with arsenic trioxide. Leuk Lymphoma 54:2041–2046CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Zdenka Šlejkovec
    • 1
  • Helena Podgornik
    • 2
  • Peter Černelč
    • 2
  • Ingrid Falnoga
    • 1
  1. 1.Jožef Stefan InstituteLjubljanaSlovenia
  2. 2.University Medical Centre LjubljanaLjubljanaSlovenia

Personalised recommendations