Effects of paraoxonase 1 activity and gene polymorphisms on long-term pulmonary complications of sulfur mustard-exposed veterans Ali Taravati a , Sussan K. Ardestani a, ⁎, Abed-Ali Ziaee a , Atefeh Ghorbani a , Mohammad-Reza Soroush b , Soghrat Faghihzadeh c , Hadi Kazemi d, e , Abbas Rezaei f , Habibollah Hoseini g , Tooba Ghazanfari h, i a Institute of Biochemistry and Biophysics, Tehran University, Tehran, Islamic Republic of Iran b Janbazan Medical and Engineering Research Center (JMERC), Tehran, Islamic Republic of Iran c Department of Biostatistics and Social Medicine, Zanjan University of Medical Sciences, Zanjan, Islamic Republic of Iran d Shafa Neuroscience Research Center, Tehran, Islamic Republic of Iran e Dep of Pediatrics, Shaheed Mostafa Khomeini Hospital, Shahed University, Tehran, Islamic Republic of Iran f Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Islamic Republic of Iran g Isfahan University of Medical Sciences, Isfahan, Islamic Republic of Iran h Immunoregulation Research Center, Shahed University, Tehran, Islamic Republic of Iran i Department of Immunology, Shahed University, Tehran, Islamic Republic of Iran abstract article info Article history: Received 2 February 2012 Received in revised form 12 November 2012 Accepted 27 December 2012 Available online 29 January 2013 Keywords: Sulfur mustard Paraoxonase 1 Oxidative Stress Pulmonary problems Sulfur mustard (SM) is an alkylating agent with prolonged adverse effects. The antioxidant paraoxonase 1 (PON1), an endogenous free radical scavenger, plays a protective role against oxidative stress. The possible roles of oxidative stress in the pathogenesis of SM, together with the antioxidant activity of PON1, are enough to warrant the analysis of PON1 polymorphisms and allelic variants in incapacitated veterans. PON1 55 L/M and 192 Q/R polymorphisms were assayed in 289 male veterans with severe pulmonary conditions, who were exposed to SM 20–25 years ago, and 66 gender-, age- and ethnic-matched healthy controls. As we showed previously the PON1 activity decreased significantly in veterans. However, PON1 55 L/M and 192 Q/R genotype distributions were not significantly different between the veterans and the controls. R and L allele carriers have also significantly higher basal and salt-stimulated PON1 activity than Q and M allele carriers. Paraoxonase and arylesterase activities in individuals with the QQ + (MM or LM) genotype were significantly lower than those with the (RR or QR) + LL genotype. Furthermore, basal and salt-stimulated paraoxonase activity in veterans with the (RR or QR) + LL genotype was significantly lower than that in the controls. A positive correlation has been determined between serum PON1 activity and pulmonary func- tion test in QR/LL genotypes. Some of the veterans with RR + QR genotypes have also shown a novel missense change of Asn227Ser in exon 6 of the enzyme. This substitution is close to the binding domain of PON1 and so modifies enzyme activity. © 2013 Elsevier B.V. All rights reserved. 1. Introduction SM is a powerful vesicant (alkylating agent) with strong cytotoxic properties. It was used extensively during World War I and the Iraq– Iran conflict. Early effects of SM on veterans have been investigated, but there is no comprehensive information concerning the chronic/ long-term effects. However, SM-induced toxicity affecting the eyes, skin, and respiratory tract still persist in veterans, many years after exposure to SM. It is proposed that oxidative stress plays an impor- tant part in SM intoxication, resulting in the oxidation of the most im- portant macromolecules. Human serum PON1, located on high density lipoprotein (HDL), prevents the oxidation of LDL and HDL both in vivo and in vitro through the hydrolysis of lipid peroxides [1,2]. The activity of PON1 is subjective to genetic and environmental influences, such as diet, lifestyle, smoking, environmental toxic factors, and physiological and pathological conditions [3]. PON1 seems to contribute to the inhi- bition of oxidative processes; therefore the study of PON1 activity may prove effective against disease progression in victims of chemical warfare. PON1 enzyme activity is modulated by a number of polymorphisms in the PON1 gene located on chromosome 7q21.3, which is clustered with at least two other related genes, PON2 and PON3. There is variation in the capacity of PON1 to hydrolyze different substrates. These differ- ences arise from several single nucleotide polymorphisms (SNPs) in coding and non-coding regions. The polymorphism of paraoxonase (A/G) results in glutamine (Q) to arginine (R) substitution at codon International Immunopharmacology 17 (2013) 974–979 ⁎ Corresponding author at: Institute of Biochemistry and Biophysics, Tehran University, P.O. Box 13145-1384, Tehran, Islamic Republic of Iran. Tel.: +98 21 66956976; fax: +98 21 66404680. E-mail address: ardestani@ibb.ut.ac.ir (S.K. Ardestani). 1567-5769/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.intimp.2012.12.026 Contents lists available at ScienceDirect International Immunopharmacology journal homepage: www.elsevier.com/locate/intimp