Polymorphisms in CYP-mediated arachidonic acid routes affect the outcome of renal transplantation Guillermo Gervasini * , Montserrat Garc  ıa-Cerrada * , Esther Vergara † , Guadalupe Garc  ıa-Pino ‡ , Raul Alvarado ‡ , Maria Jes  us Fern andez-Cavada † , Sergio Barroso ‡ , Emilio Doblar e ‡ and Juan Jos e Cubero † * Department of Medical and Surgical Therapeutics, Division of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain, † Service of Immunology, Infanta Cristina University Hospital, ‡ Service of Nephrology, Infanta Cristina University Hospital, Badajoz, Spain ABSTRACT Background Arachidonic acid (AA) is metabolized by cytochrome P450 (CYP) enzymes to vasoactive metabolites (mainly epoxyeicosatrienoic acids) which are known to play a protective role against damaging processes that may occur after re-oxygenation of the graft. We aimed to investigate whether the presence of functional polymorphisms along these metabolic routes may play a role in the outcome of renal transplantation. Design One-hundred and forty Caucasian renal transplant recipients and 137 donors were included. We determined the presence of seven common functional polymorphisms in the five genes governing the CYP- mediated AA metabolic pathway (CYP2C8, CYP2C9, CYP2J2, CYP4A11 and CYP4F2). Associations with parameters and events related to graft function and survival were retrospectively investigated throughout the first year after grafting. Results The CYP2J2*7 allele of the donor was significantly associated with higher risk for delayed graft func- tion [OR = 4Á40 (1Á45–13Á37), P < 0Á01] and lower death-censored graft survival [107Á90 (84Á19–131Á62) vs. 176Á89 (166Á47–187Á32) months for CYP2J2*1/*1 grafts; log-rank P = 0Á015]. In addition, patients whose donors carried the CYP4A11 434S variant of the F434S polymorphism displayed impaired creatinine clearance, with statistically significant differences vs. 434FF subjects throughout the whole period of study (P < 0Á05, P < 0Á01, P < 0Á001 and P < 0Á05 for 1 week, 1 month, 5 months and 1 year after grafting, respectively). Conclusions Taken together, these results indicate that variability in the CYP450 genes involved in the syn- thesis of eicosanoids from AA may have a significant impact on graft function and survival in renal transplan- tation. Keywords Creatinine clearance, CYP450, delayed graft function, graft survival, polymorphisms, renal transplant. Eur J Clin Invest 2015; 45 (10): 1060–1068 Introduction A variety of factors may contribute to impaired kidney allograft function by acting through inflammation and tissue injury mediated by endothelial dysfunction and activation. Endo- thelial cells produce endothelium-derived hyperpolarizing fac- tors that maintain vascular homeostasis. Among these com- pounds, there are epoxyeicosatrienoic acids (EETs), which are the product of cytochrome P450 (CYP)-mediated arachidonic acid (AA) metabolism (Fig. S1). These metabolites are involved in the intracellular transport of electrolytes, have profibrinolytic and anti-inflammatory effects and maintain vascular smooth muscle tone with vasodilator properties [1,2]. In addition, a parallel metabolic route from AA is mediated by CYP hydrox- ylases to synthesize hydroxyeicosatetraenoic acids (HETEs), most importantly 20-HETE, which may increase blood pressure by vasoconstriction or, paradoxically, promote antihyperten- sion by increasing sodium excretion in the kidney [3]. In humans, CYP2C9 and, most importantly, CYP2C8 and CYP2J2 appear to be largely responsible for the EETs formation in several organs including the kidney [4–7]. In turn, 20-HETE synthesis is mainly catalysed by CYP4A11 and CYP4F2 [8]. Each of these CYP genes is expressed in the kidney and pre- sents functional single nucleotide polymorphisms (SNPs) with the potential to modulate the effect of these active AA metabolites [9–15]. In the last years, a great number of studies seem to indicate that the metabolites of AA generated by CYP enzymes may 1060 ª 2015 Stichting European Society for Clinical Investigation Journal Foundation DOI: 10.1111/eci.12507 ORIGINAL ARTICLE