Paracetamol (Acetaminophen) and the Developing Brain

Abstract

Paracetamol is commonly used to treat fever and pain in pregnant women, but there are growing concerns that this may cause attention deficit hyperactivity disorder and autism spectrum disorder in the offspring. A growing number of epidemiological studies suggests that relative risks for these disorders increase by an average of about 25% following intrauterine paracetamol exposure. The data analyzed point to a dose-effect relationship but cannot fully account for unmeasured confounders, notably indication and genetic transmission. Only few experimental investigations have addressed this issue. Altered behavior has been demonstrated in offspring of paracetamol-gavaged pregnant rats, and paracetamol given at or prior to day 10 of life to newborn mice resulted in altered locomotor activity in response to a novel home environment in adulthood and blunted the analgesic effect of paracetamol given to adult animals. The molecular mechanisms that might mediate these effects are unknown. Paracetamol has diverse pharmacologic actions. It reduces prostaglandin formation via competitive inhibition of the peroxidase moiety of prostaglandin H2 synthase, while its metabolite N-arachidonoyl-phenolamine activates transient vanilloid-subtype 1 receptors and interferes with cannabinoid receptor signaling. The metabolite N-acetyl-p-benzo-quinone-imine, which is pivotal for liver damage after overdosing, exerts oxidative stress and depletes glutathione in the brain already at dosages below the hepatic toxicity threshold. Given the widespread use of paracetamol during pregnancy and the lack of safe alternatives, its impact on the developing brain deserves further investigation.

Keywords: acetaminophen; attention deficit hyperactivity disorder; autism spectrum disorder; paracetamol.

Figure 1

Paracetamol metabolites. NAPQI: N-acetyl-p-benzo-quinone-imine; UGT: UDP-glucuronyl transferase; SULT: sulfotransferase; N-DAC: N-deacetylase; GST: glutathione S-transferase; p-BQI: p-benzoquinone; FAAH: fatty acid amide hydrolase; AM404: N-arachidonoyl-phenolamine.

Figure 2

Paracetamol metabolism and pharmacology. Unchanged paracetamol (acetaminophen) is excreted in the urine to a small extent. It may also act as an antagonist of the vanilloid-subtype 4 receptors (TRPV4) in various tissues. Paracetamol is mainly metabolized in the liver. The metabolites generated by glucuronidation and sulfation are not toxic and subject to urinary excretion, while a minor fraction undergoes oxidative metabolism. This results in formation of N-acetyl-p-benzo-quinone-imine (NAPQI), a highly toxic intermediary produced by cytochrome P450 enzymes. NAPQI builds adducts with mitochondrial proteins and induces oxidative stress, nuclear DNA fragmentation, and subsequent cell necrosis. Paracetamol is becoming de-acetylated to p-aminophenol, which in turn is metabolized by the hepatic microsomal cytochrome P450 enzyme system to the toxic compound p-benzoquinone (p-BQI). Under physiological conditions, detoxification of NAPQI and p-BQI occurs by binding to glutathione (GSH) and subsequent renal excretion. The prostaglandin endoperoxide H synthase (PGHS) complex consists of a cyclooxygenase (COX) and a peroxidase (POX) moiety. Arachidonic acid is first transformed to the unstable prostaglandin G₂ (PGG₂) by COX, which is further reduced to prostaglandin H₂ (PGH₂) by POX. PGH₂ gives rise to various endogenous regulators such as prostaglandins, prostacyclins, and thromboxane. Paracetamol induces analgesia and antipyresis by blocking prostaglandin synthesis at the POX site of PGHS complex. p-aminophenol undergoes conjugation with arachidonic acid by fatty acid amide hydrolase (FAAH) to N-arachidonoyl-phenolamine (AM404), which is a potent activator of TRPV1 and transient receptor potential ankyrin 1 (TRPA1) as well as a weak agonist of cannabinoid receptors type 1 and 2 (CBR1/2). Activation of these receptors by AM404 may mediate analgesic effects. NAPQI and p-BQI may also produce analgesic and antipyretic effects by activating TRPA1. UGT: UDP-glucuronyl transferase; SULT: sulfotransferase; N-DAC: N-deacetylase; GST: glutathione S-transferase.