Sulphation deficit in “low-functioning” autistic children: a pilot study

doi:10.1016/S0006-3223(98)00337-0

Biological Psychiatry

Volume 46, Issue 3, 1 August 1999, Pages 420-424

https://doi.org/10.1016/S0006-3223(98)00337-0 Get rights and content

Abstract

Background: Parents of autistic children and autism support groups often report that autistic episodes are exacerbated when the children eat certain foodstuffs such as dairy products, chocolates, wheat, corn sugar, apples, and bananas. The hypothesis that autistic behavior might be related to metabolic dysfunctions has led us to investigate in a group of “low functioning” autistic children and in an age-matched control group each made up of 20 subjects, the sulphation capacity available.

Methods: Utilizing the biochemical characteristics of paracetamol we evaluated by high performance liquid chromatography, the urine paracetamol–sulfate/paracetamol-glucuronide (PS/PG) ratio in all subjects following administration of this drug.

Results: The PS/PG ratio in the group of autistic subjects gave a significantly lower result than the control group with p < .00002.

Conclusions: The inability to effectively metabolize certain compounds particularly phenolic amines, toxic for the CNS, could exacerbate the wide spectrum of autistic behavior.

Introduction

It has been hypothesized that autistic children might have metabolic dysfunctions, and that some substances contained in the food they ingest make them behave in an autistic manner. Parents and autism support groups often report that the autistic episodes are exacerbated when the children eat certain foodstuffs such as dairy products, wheat, corn, sugar, apples, bananas, and chocolate. This has led to the belief that autism could be allergy induced Rapp 1978, Rapp 1980, O’Banion 1978, Knivsberg et al 1990.

Preliminary studies have demonstrated that these children have a compromised capacity for sulphoconjugation and therefore, are unable to effectively metabolize numerous compounds particularly phenolic amines such as dopamine, tyramine, and serotonin (present in many foodstuffs), which function as neurotransmitters (Ngong 1994). These substances are normally metabolized into nontoxic, water soluble, readily excreted metabolites through a detoxification process of conjugation with sulphate in the gastrointestinal tract and in the liver after absorption, or by monoamine oxidase activity. Other detoxification processes include conjugation with glucuronic acid.

Paracetamol (4-acetylaminophenol, acetaminophen) is a well known, widely used analgesic and antipyretic drug. It contains a phenolic grouping that is normally conjugated with glucuronic acid or sulphate before excretion in the urine. The glucuronic acid residue is transferred via UDPGA (uridine diphosphate glucuronic acid) and the microsomal glucuronyl transferase enzymes, while sulphoconjugation (addition of sulphonate, SO₃²⁻, residue) occurs via PAPS (3′-phosphoadenosine-5′-phosphosulphate) as an active carrier of sulphate and the cytosolic sulphotransferase enzymes. Both these pathways give metabolites that are more water soluble, more readily excreted, and less toxic than the parent, paracetamol. Because pure reference metabolites are not readily available, paracetamol glucuronide and paracetamol sulphate are measured by following the increase in paracetamol when the conjugates are hydrolysed by β-glucuronidase or sulphatase (both hydrolytic enzymes), respectively. In any individual, although absolute amounts of the metabolites may vary over time, the ratio of the paracetamol sulphate excreted to paracetamol glucuronide is constant and the use of the PS/PG ratio enables metabolism to be compared over a population Bonham Carter 1983, Rona et al 1994. Paracetamol has been used as a “probe” drug to estimate the relative contributions of glucuronide and sulphate pathways in a number of clinical dysfunctional states Bradley et al 1991, Steventon et al 1990, Al-Obaidy et al 1996, Dolara et al 1987. The aim of our study was to use the biochemical characteristics of paracetamol to evaluate the sulphation capacity available for the process of detoxification through sulphoconjugation in a significant number of autistic children and in a control group.

Section snippets

Methods and materials

We examined a group of 60 patients (49M, 11F) aged 2.7 to 15.0 years (mean age 10.3, SD 3.61) affected by autistic disorder. The other types of pervasive developmental disorders were excluded from the study. Diagnosis was based on DSM-IV criteria; interview with the families; direct observation of the patients during the various moments of the day; and application of CARS scale. Griffith developmental scales, Brunet-Lezine, Vineland, and PEP-R tests. We also examined 20 volunteers aged 3.2 to

Results

Among the 20 age-matched “low-functioning” autistic subjects, 18 out of 20 had a PS/PG ratio ≤ to 1.5, with a mean of 1.1109 and SD 0.7449 (Figure 1, column C); whereas in the control group, 19 out of 20 had a PS/PG ratio ≥ to 1.5 (Table 1), with a mean of 3.1515 and SD 1.674 (Figure 1, column D). The two groups, each made up of 20 subjects, were statistically compared. After a preliminary evaluation of the distribution of normal values, utilizing Kolgomorov-Smirnov, Lilliefors, and

Discussion

Phenolic amines are normally conjugated through a process of sulphation in the CNS. In humans, this pathway appears to be more significant than glucuronidation (Tyce et al 1986). Sulphotransferase enzymes catalyse sulphation of phenols (P-form) and amines (M-form), though both variants will sulphate the alternative substrate at higher concentration (Coughtrie 1996). There are no gender effects; there is a small age effect (controlled for in the present study) where sulphation is slightly

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Original ArticlesSulphation deficit in “low-functioning” autistic children: a pilot study

Abstract

Introduction

Section snippets

Methods and materials

Results

Discussion

Pharmacol Res Comm

Toxicol Lett

Biol Psychiatry

Lancet

Metabolism of paracetamol in children with chronic liver disease

Eur J Clin Pharmacol

Human platelet phenolsulphotransferase M and PSubstrate specificities and correlation with in vivo sulphoconjugation of paracetamol and salicylamide

Br J Clin Pharmacol

Metabolism of low-dose paracetamol in patients with rheumatoid arthritis

Xenobiotica

Sulphation catalysed by human cytosolic sulphotranferases-chemical defence or molecular terrorism

Hum Exp Toxicol

Dietary modulation of human platelet phenol sulphotransferase activity

Xenobiotica

Paracetamol metabolism following overdosageApplication of high performance liquid chromatography

J Pharm Pharmacol

Original Articles
Sulphation deficit in “low-functioning” autistic children: a pilot study