title: Can creatine supplementation form carcinogenic heterocyclic amines in humans?
abstract: There is a long-standing concern that creatine supplementation could be associated with cancer, possibly by facilitating the formation of carcinogenic heterocyclic amines (HCAs). This study provides compelling evidence that both low and high doses of creatine supplementation, given either acutely or chronically, does not cause a significant increase in HCA formation. HCAs detection was unrelated to creatine supplementation. Diet was likely to be the main factor responsible for HCAs formation after either placebo (n = 6) or creatine supplementation (n = 3). These results directly challenge the recently suggested biological plausibility for the association between creatine use and risk of testicular germ cell cancer. Creatine supplementation has been associated with increased cancer risk. In fact, there is evidence indicating that creatine and/or creatinine are important precursors of carcinogenic heterocyclic amines (HCAs). The present study aimed to investigate the acute and chronic effects of low- and high-dose creatine supplementation on the production of HCAs in healthy humans (i.e. 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx), 2-amino-(1,6-dimethylfuro[3,2-e]imidazo[4,5-b])pyridine (IFP) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx)). This was a non-counterbalanced single-blind crossover study divided into two phases, in which low- and high-dose creatine protocols were tested. After acute (1 day) and chronic supplementation (30 days), the HCAs PhIP, 8-MeIQx, IFP and 4,8-DiMeIQx were assessed through a newly developed HPLC-MS/MS method. Dietary HCA intake and blood and urinary creatinine were also evaluated. Out of 576 assessments performed (from 149 urine samples), only nine (3 from creatine and 6 from placebo) showed quantifiable levels of HCAs (8-MeIQx: n = 3; 4,8-DiMeIQx: n = 2; PhIP: n = 4). Individual analyses revealed that diet rather than creatine supplementation was the main responsible factor for HCA formation in these cases. This study provides compelling evidence that both low and high doses of creatine supplementation, given either acutely or chronically, did not cause increases in the carcinogenic HCAs PhIP, 8-MeIQx, IFP and 4,8-DiMeIQx in healthy subjects. These findings challenge the long-existing notion that creatine supplementation could potentially increase the risk of cancer by stimulating the formation of these mutagens.
authors.affiliation: School of Physical Education and Sport, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Renato Tavares dos Santos
authors.initials: RT
authors.lastname: Pereira
authors.affiliation: Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Felipe Augusto
authors.initials: FA
authors.lastname: Dörr
authors.affiliation: Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Ernani
authors.initials: E
authors.lastname: Pinto
authors.affiliation: School of Physical Education and Sport, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Marina Yazigi
authors.initials: MY
authors.lastname: Solis
authors.affiliation: School of Physical Education and Sport, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Guilherme Giannini
authors.initials: GG
authors.lastname: Artioli
authors.affiliation: School of Physical Education and Sport, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Alan Lins
authors.initials: AL
authors.lastname: Fernandes
authors.affiliation: School of Physical Education and Sport, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Igor Hisashi
authors.initials: IH
authors.lastname: Murai
authors.affiliation: School of Physical Education and Sport, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Wagner Silva
authors.initials: WS
authors.lastname: Dantas
authors.affiliation: School of Medicine, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Antônio Carlos
authors.initials: AC
authors.lastname: Seguro
authors.affiliation: School of Medicine, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Mirela Aparecida Rodrigues
authors.initials: MA
authors.lastname: Santinho
authors.affiliation: School of Physical Education and Sport, University of Sao Paulo, Sao Paulo, Brazil.|School of Medicine, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Hamilton
authors.initials: H
authors.lastname: Roschel
authors.affiliation: Faculty of Motor Sciences, Université of libre de Bruxelles, Belgium.
authors.forename: Alain
authors.initials: A
authors.lastname: Carpentier
authors.affiliation: Faculty of Motor Sciences, Université of libre de Bruxelles, Belgium.
authors.forename: Jacques Remi
authors.initials: JR
authors.lastname: Poortmans
authors.affiliation: School of Physical Education and Sport, University of Sao Paulo, Sao Paulo, Brazil.|School of Medicine, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Bruno
authors.initials: B
authors.lastname: Gualano
mesh_terms: D000328:Adult; D000588:Amines; D002273:Carcinogens / Q000378:metabolism*; D003401:Creatine / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D018592:Cross-Over Studies; D004032:Diet; D005260:Female; D005663:Furans / Q000652:urine*; D006801:Humans; D007093:Imidazoles / Q000652:urine*; D008297:Male; D011810:Quinoxalines / Q000652:urine*; D016037:Single-Blind Method
chemical_list: C412490:2-amino-(1,6-dimethylfuro(3,2-e)imidazo(4,5-b))pyridine; D000588:Amines; D002273:Carcinogens; D005663:Furans; D007093:Imidazoles; D011810:Quinoxalines; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D003401:Creatine; C045421:3,4,8-trimethylimidazo(4,5-f)quinoxalin-2-amine