No Association of AS3MT Gene Polymorphisms with Susceptibility to Hepatotoxicity and in APL Patients Treated with AS2O3: A Single Center Study

Zeinab Joneidi; Yousef Mortazavi; Bahram Chahardouli; Shahrbano Rostami; Mohammad Vaezi; Majid Nabipour; Alireza Biglari; Ardeshir Ghavamzadeh

doi:10.18502/ijhoscr.v17i4.13920

Zeinab Joneidi Department of Genetics and Molecular Medicine, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
Yousef Mortazavi Department of Biotechnology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
Bahram Chahardouli Cell Therapy and Hematopoietic Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
Shahrbano Rostami Research Institute for Oncology, Hematology and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran
Mohammad Vaezi Cell Therapy and Hematopoietic Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
Majid Nabipour Department of Internal Medicine, School of Medicine, Babol University of Medical Sciences, Babol, Tehran
Alireza Biglari Department of Genetics and Molecular Medicine, School of Medicine, Cancer Gene Therapy Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
Ardeshir Ghavamzadeh Cancer & Cell Therapy Research Center, Tehran University of Medical Sciences, Tehran, Iran

DOI: https://doi.org/10.18502/ijhoscr.v17i4.13920

Keywords: Acute promyelocytic leukemia (APL); Hepatotoxicity; Polymorphism

Abstract

Background: Arsenic three oxide (As2O3) is the treatment choice for acute promyelocytic leukemia (APL). Little is known about possible risk factors with predictive value for toxicity caused by As2O3. Biomethylation is considered to be a major pathway of detoxification for inorganic arsenics (iAs). Arsenic Methyltransferase (AS3MT) is one of the key enzymes involved in the transfer of a methyl group from S-adenosyl-L-methionine to trivalent arsenical and plays a critical role in arsenic detoxification. Polymorphisms in hAS3MT lead to a change in the catalytic activity of the enzyme and may increase the risk of arsenic-related toxicity. In this study, we investigated the association of the AS3MT polymorphisms (rs11191439, rs3740390, and rs3740393) genes with hepatotoxicity in APL patients treated with As2O3.

Materials and Methods: Genotyping was performed in 140 adult patients with APL treated with As2O3 using PCR-RFLP for rs11191439 and tetra-primer ARMS-PCR for rs3740390 and rs3740393. The results of PCR-RFLP and ARMS-PCR were confirmed by direct sequencing of 10 % of DNA samples. The results were analyzed using SNPStats, SPSS, and FinchTV. Hepatotoxicity was graded according to the National Cancer Institute's Common Toxicity Criteria (CTC).

Results: Hepatotoxicity was seen in 52 of the 140 patients (37.1%), with grades I and II hepatotoxicity in 40 (28.6%) and grades III and IV hepatotoxicity in 12 (8.5%) patients. The association between the three polymorphisms and hepatotoxicity was evaluated using five genetic models and none of the three studied polymorphisms were significantly associated with hepatotoxicity.

Discussion: The results of our study showed that AS3MT rs11191439, rs3740390, and rs3740393 polymorphisms are not associated with hepatotoxicity in APL patients. Genetic polymorphisms in enzymes which are involved in arsenic metabolism have been shown to have ethnicity and race-related differences. To more precisely characterize the association between AS3MT gene polymorphism and hepatotoxicity, future large-scale studies in non-Asian populations and other ethnicities are needed.