Volume 2 • Issue 4 • 1000e148 Biochem & Pharmacol ISSN: 2167-0501 BCPC, an open access journal Editorial Open Access Abdin, Biochem & Pharmacol 2013, 2:4 DOI: 10.4172/2167-0501.1000e148 Keywords: Acetaminophen; Autism; N-acetylp-benzoquinoneimine (NAPQI) Autism is a developmental disorder defned by social and communication defcits and ritualistic-repetitive behaviors that appear in early childhood [1] Autism is complex and heterogeneous in origin and proposed to be due to interaction of genetic and environmental factors [2]. Te incidence of autism has risen ~10-fold since the early 1980s, with most of this rise not explainable by changing diagnostic criteria. Is there any explanation for that? Clinical and epidemiological studies and post-market pharmacovigilence are of utmost importance in detection of unrecognized or missed drug-induced side efects. Acetaminophen (paracetamol) is a widely used over-the-counter (OTC) analgesic and antipyretic that was introduced since 1955 [3]. Unfortunately the recent mechanistic evidence suggests correlation between acetaminophen exposure and increased incidence and risk of autism [4-6]. Considerable evidence supports this contention, most notably the exponential chronological rise in acetaminophen consumption for infants and young children since 1980s when it began to replace aspirin [7]. For instance, this compound has been taken, at least once, by more than 85% of children under the age of 91 months in the UK [8]. Children who are poor metabolizrs of acetaminophen may be at higher risk even under therapeutic doses [5]. Tere are four major pathways for acetaminophen detoxifcation namely; the major pathways of glucuronidation or deacetylation to a phenol, and sulfation catalyzed by phenolsulfotransferase, and the minor toxic pathway by the cytochrome P450 (CYP2E1) enzyme producing N-acetylp- benzoquinone imine (NAPQI) Glucuronidation is commonly present at low capacity in the fetus, newborns, and young infants, such that exposure to acetaminophen at these times leads to greater metabolism by other pathways [9]. One key piece of evidence came from the observation that sulfation pathway catalyzed by phenolsulfotransferase is proved to be defcient in autism. Tis leads to overproduction of the toxic metabolite NAPQI from acetaminophen with a subsequent depletion of glutathione the main source of sulfydryl groups with reduction in the ability to detoxify a host of toxic chemicals in the environment, increasing oxidative stress, which leads to protein, lipid, and nucleic acid damage from free radicals [5]. Te characteristic loss of Purkinje cells in the brains of autistic cases is consistent with depletion of brain glutathione and as of 2012; there are many articles that indicated an association between toxic chemical exposure and autism. For example, exposure to NAPQI derived from acetaminophen, competitively inhibits the reaction of metals (such as mercury) with the sulfydryl groups in children with autism [10]. Importantly, NAPQI also inhibits the isomerase and the biological activities of macrophage migration inhibitory factor (MIF) [11]. Polymorphism of MIF has recently been associated with autism spectrum disorders (ASDs) [8]. In addition, oxidative damage of mitochondrial proteins and DNA by acetaminophen leads to activation of DNase (s) which is typically responsible for nuclear DNA fragmentation and apoptosis [12]. Tere are several studies had shown an association between mitochondrial dysfunction and apoptosis with autism [13]. Also, cetaminophen has been found to induce apoptosis-dependent neurotoxicity by increasing neuronal CYP2E1 enzymatic activity, leading to neuronal death through mitochondrial mediated mechanisms that involve cytochrome c release and caspase-3 activation. One of the prominent features of autism is immune system dis-ccregulation [14]. Recently, acetaminophen has been postulated to provoke autism through neuro- immunomodulatory efect that may be mediated by activation of endocannabinoids system. Acetaminophen metabolite p-aminophenol can conjugate with arachidonic acid in the brain and spinal cord resulting in inhibition of the cellular uptake of anandamide, a naturally occurring endocannabinoid [15]. Te cannabinoid CB2 receptors are primarily located in immune tissues and cells and may serve a regulatory function [16]. To this point of information, safety of acetaminophen becomes questionable and acetaminophen/autism alarm should be paid more attention. References 1. Caine ED, Jeffrey M, Lyness M, Jesse F, Porsteinsson AP, et al. (1994) Diagnostic and Statistical Manual of Mental Disorders. (4thedn), American Psychiatric Association, Washington DC, USA. 2. Becker KG, Schultz ST (2010) Similarities in features of autism and asthma and a possible link to acetaminophen use. Med Hypotheses 74: 7-11. 3. Schultz S (2008) Autism Risk. Saarbrücken, Germany: VDM Verlag Dr. Müller Aktiengesellschaft & Co. 4. Good P (2009) Did acetaminophen provoke the autism epidemic? Altern Med Rev 14: 364-372. 5. Schultz ST (2010) Can autism be triggered by acetaminophen activation of the endocannabinoid system? Acta Neurobiol Exp (Wars) 70: 227-231. 6. Bauer AZ, Kriebel D (2013) Prenatal and perinatal analgesic exposure and autism: an ecological link. Environ Health 12: 41. 7. Shaw W (2013) Evidence that Increased Acetaminophen use in Genetically Vulnerable Children Appears to be a Major Cause of the Epidemics of Autism, Attention Defcit with Hyperactivity, and Asthma. Journal of Restorative Medicine 2: 2-16. 8. J. Headley, K. Northstone (2007) Medication administered to children from 0 to 7.5 years in the Avon Longitudinal Study of Parents and Children (ALSPAC). Eur J Clin Pharmacol 63: 189-95. 9. Alcorn J, McNamara PJ (2003) Pharmacokinetics in the newborn. Adv Drug Deliv Rev 55: 667-686. 10. Adams JB, Romdalvik J, Levine KE, Hu LW (2008) Mercury in frst-cut baby hair of children with autism versus typically-developing children. Toxicol Environ Chem; 90: 739-53. 11.Senter PD, Al-Abed Y, Metz CN, Benigni F, Mitchell RA, et al. (2002) Inhibition of macrophage migration inhibitory factor (MIF) tautomerase and biological activities by acetaminophen metabolites. Proc Natl Acad Sci U S A 99: 144-149. *Corresponding author: Department of Pharmacology, Faculty of Medicine, Tanta University, Egypt, Tel: +2-01223700963; E-mail: amanyabdin@med.tanta.edu.eg Received December 12, 2013; Accepted December 14, 2013; Published December 23, 2013 Citation: Abdin AA (2013) Acetaminophen/Autism: Alarm?. Biochem & Pharmacol 2:e148. doi:10.4172/2167-0501.1000e148 Copyright: © 2013 Abdin AA. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Acetaminophen/Autism: Alarm? Amany A. Abdin* Department of Pharmacology, Faculty of Medicine, Tanta University, Egypt B i o c h e m i s t r y & P h a r m a c o l o g y : O p e n A c c e s s ISSN: 2167-0501 Biochemistry & Pharmacology: Open Access