Phenolic Drugs Research Articles

Omega-3 polyunsaturated lipophenols, how and why?

Polyphenols and n-3 polyunsaturated fatty acids (PUFAs) are two classes of natural compounds, which have been highlighted in epidemiological studies for their health benefits. The biological activities of those two families of metabolites on oxidation, inflammation, cancer, cardiovascular and degenerative diseases have been reported invitro and invivo. On the other hand, chemical bonding between the two structures leading to n-3 lipophenol derivatives (or phenolipids) has been studied in numerous works over the last decade, and some examples could also be found from natural sources. Interest in lipophilization of phenolic structures is various and depends on the domain of interest: in food industry, the development of lipidic antioxidants could be performed to protect lipidic food matrix from oxidation. Whereas, on pharmaceutical purpose, increasing the lipophilicity of polar phenolic drugs could be performed to improve their pharmacological profile. Moreover, combining both therapeutic aspects of n-3 PUFAs and of polyphenols in a single lipophenolic molecule could also be envisaged. An overview of the synthesis and of the natural sources of n-3 lipophenols is presented here, in addition to their biological activities which point out in several cases the benefit of the conjugated derivatives.

Preparation of Nano Silica Supported Sodium Hydrogen Sulfate: As an Efficient Catalyst for the Trimethyl, Triethyl and t‐Butyldimethyl Silylations of Aliphatic and Aromatic Alcohols in Solution and under Solvent‐free Conditions

AbstractNano silica supported sodium hydrogen sulfate has been prepared by mixing NaHSO4 with activated Nano silicagel. We wish to report a new method for the synthesis of trimethyl (TMS), triethyl (TES) and t‐butyldimethyl silyl (TBS) ethers from benzylic, allylic, propargylic alcohols, phenols, naphtholes and some of phenolic drugs in the solution and under solvent‐free conditions.

A Mild and Highly Efficient Method for the Preparation of Silyl Ethers using Fe(HSO4)3/Et3N by Chlorosilanes

AbstractA very efficient and mild procedure for preparation of silyl ethers from benzylic, allylic, propargilic alcohols, phenols, naphtoles and some of phenolic drugs with trimethylsilylchloride (TMSCl), triethylsilylchloride (TESCl) and t‐buthyldimethylsilyl chloride (TDSCl) ethers in the presence of Fe(HSO4)3/Et3N in room temperature in excellent yields is reported. This procedure also allows the excellent selectivity for silylation of alcohols and phenols.

N , N ′-Dialkylaminoalkylcarbonyl (DAAC) prodrugs and aminoalkylcarbonyl (AAC) prodrugs of 4-hydroxyacetanilide and naltrexone with improved skin permeation properties

N,N'-Dialkylaminoalkylcarbonyl (DAAC) and aminoalkylcarbonyl (AAC) prodrugs of phenolic drugs acetaminophen (APAP) and naltrexone (NTX) are reported. The effects of incorporation of a basic amine group into the promoiety of an acyl prodrug of a phenolic drug on its skin permeation properties are also presented. DAAC-APAP prodrugs were synthesized via a three-step procedure starting with haloalkylcarbonyl esters which were reacted with five different amines: dimethylamine, diethylamine, dipropylamine, morpholine, and piperidine. The spacing between the amino group and the carbonyl group of the acyl group was 1-3 CH(2). After the hydrolysis of the ester, the carboxylic acid product was subsequently coupled with the parent drug via a dicyclohexyl carbodiimide (DCC) mediated coupling to yield the DAAC-APAP-HCl prodrugs in excellent yields. The AAC prodrugs were synthesized using commercially available Boc-protected amino acids using DCC or EDCI as coupling agents. The yields of the prodrugs synthesized using these two different methods have been compared. Half-lives (t(1/2)) of a few members of the DAAC and AAC series were measured in buffer (pH 6.0, 20mM). The members evaluated in hydrolysis experiments exhibit a t(1/2) range of 15-113min. Among AAC-APAP prodrugs, the isopropyl group in valinate-APAP-HCl exerted a steric effect that increased the t(1/2) value for this prodrug compared to alaninate-APAP-HCl or prolinate-APAP-HCl. The 2-morpholinylacetate-APAP prodrug was able to achieve twice the flux of APAP in in vitro diffusion cell experiments through hairless mouse skin.

Evolution of a Major Drug Metabolizing Enzyme Defect in the Domestic Cat and Other Felidae: Phylogenetic Timing and the Role of Hypercarnivory

The domestic cat (Felis catus) shows remarkable sensitivity to the adverse effects of phenolic drugs, including acetaminophen and aspirin, as well as structurally-related toxicants found in the diet and environment. This idiosyncrasy results from pseudogenization of the gene encoding UDP-glucuronosyltransferase (UGT) 1A6, the major species-conserved phenol detoxification enzyme. Here, we established the phylogenetic timing of disruptive UGT1A6 mutations and explored the hypothesis that gene inactivation in cats was enabled by minimal exposure to plant-derived toxicants. Fixation of the UGT1A6 pseudogene was estimated to have occurred between 35 and 11 million years ago with all extant Felidae having dysfunctional UGT1A6. Out of 22 additional taxa sampled, representative of most Carnivora families, only brown hyena (Parahyaena brunnea) and northern elephant seal (Mirounga angustirostris) showed inactivating UGT1A6 mutations. A comprehensive literature review of the natural diet of the sampled taxa indicated that all species with defective UGT1A6 were hypercarnivores (>70% dietary animal matter). Furthermore those species with UGT1A6 defects showed evidence for reduced amino acid constraint (increased dN/dS ratios approaching the neutral selection value of 1.0) as compared with species with intact UGT1A6. In contrast, there was no evidence for reduced amino acid constraint for these same species within UGT1A1, the gene encoding the enzyme responsible for detoxification of endogenously generated bilirubin. Our results provide the first evidence suggesting that diet may have played a permissive role in the devolution of a mammalian drug metabolizing enzyme. Further work is needed to establish whether these preliminary findings can be generalized to all Carnivora.

Prodrug Design of Phenolic Drugs

Phenolic group in therapeutic drugs can be used for a prodrug modification to overcome various undesirable drug properties that may become pharmacological, pharmaceutical or pharmacokinetic barriers for application. Several strategies have been used in order to overcome the limited bioavailability of phenolic drugs. Classical design represents a nonspecific chemical approach to mask undesirable drug properties, limited bioavailability or chemical instability. Targeted prodrug design represents a new strategy for directed and efficient drug delivery. Particularly, targeting the prodrug to specific enzyme or specific membrane transporter has potential as selective drug delivery system mainly in cancer therapy. The article brings examples of ester, sulphate, carbamate, carbonate, phosphate and ether prodrugs as well as the limitations of these prodrug strategies. Some specific enzyme targets are also presented.

Design and Development of Nanovehicle-Based Delivery Systems for Preventive or Therapeutic Supplementation with Flavonoids

To date more than 4000 compounds are recognized to belong to the class of flavonoids. These natural phenolic drugs are poorly soluble in water and are rapidly degraded and metabolized in the human body, but nevertheless are very promising for their potential contribution to the prevention and therapy of major chronic diseases, including cardiovascular and neurodegenerative diseases and cancer. In recent years a number of flavanols (e.g. catechins), flavonols (e.g. quercetin, myricetin) and isoflavones (e.g. genistein, daidzein) have been confirmed to possess strong antioxidant, anti-inflammatory, anti-proliferative and anti-aging activities. Incorporation into lipidic or polymer-based nanoparticles appears to markedly help the oral delivery of flavonoids, as these particles can protect the drug from degradation in the gastrointestinal tract and, by virtue of their unique absorption mechanism through the lymphatic system, also from first-pass metabolism in the liver. In addition, both oral and parenteral administration of flavonoids exploits a pharmacologic delivery route that guarantees sustained release of the active principle at the desired site of action. A comprehensive review of studies currently available on the in vitro and in vivo experimental administration of flavonoids by means of nanovectors may be of use as a foundation for the development of advanced delivery systems for these powerful compounds, in view of their adoption in primary and secondary disease prevention.

Spectrophotometric Method for the Determination of Drugs Containing Phenol Group by Using 2, 4‐ Dinitrophenylhydrazine

A spectrophotometric method has been proposed for the determination of four phenolic drugs; salbutamol, ritodrine, amoxicillin and isoxsuprine. The method is based on the oxidation of 2, 4‐ dinitrophenyl‐hydrazine and coupling of the oxidized product with drugs to give intensely colored chromogen. Under the proposed optimum condition, beer’s law was obeyed in the concentration range of 2.5‐17, 2‐29, 4‐33 and 5‐30 μg/mL for salbutamol, ritodrine, amoxicillin and isoxsuprine respectively. The limit of detection (LOD) and limit of quantification (LOQ) were 0.2, 0.83, 0.09, 0.84 μg/mL and 0.66, 2.79, 0.3 and 2.81 μg/mL in the same order. No interference was observed from common pharmaceutical adjuvants. The ringbom plots and low relative standard deviation assert the applicability of this method. The suggested method was further applied for the determinations of drugs in commercial pharmaceutical dosage forms, which was compared statistically with reference methods by means of t‐ test and F‐ test and were found not to differ significantly at 95% confidence level. The procedure is characterized by its simplicity with accuracy and precision.

Use of RP-TLC and theoretical computational methods to compare the lipophilicity of phenolic drugs

The chromatographic behavior of the phenolic drugs niclosamide, hexachlorophene, ibuprofen, pentazocine, ethamivan, bithionol, salicylanilide, caffeic acid, p -coumaric acid, 4-aminosalicylic acid, ferulic acid, and methyldopa has been investigated on RP8F 254s and RP18F 254s TLC plates with methanol-water mixtures in different volume proportions as mobile phases. Linear relationships were obtained between the R M values of the drugs and the volume fraction of methanol in the mobile phase. Retention values, R M , were extrapolated to zero methanol content and the lipophilicity values R MW(RP8) and R MW(RP18) obtained were compared both with measured partition coefficients (log P exp ) and with partition coefficients (AlogPs, IAlogP, AB/logP, COSMOFFrag, miLogP, KOWWIN, and xlogP) calculated using seven different software products. Comparison of the calculated partition coefficients revealed IAlogP, KOWWIN, miLogP, and \documentclass{aastex} \usepackage{amsbsy} \usepackage{amsfonts} \usepackage{amssymb} \u...

Quantitative In Silico Analysis of Ion Exchange from Chromatography to Protein

Molecular interaction forces are based on solubility factors. Coulombic force is the strongest, followed by the Lewis acid‐base interaction, including hydrogen bonding and charge‐transfer effects, and van der Waals forces. Steric hindrance affects the molecular interaction. The individual interaction force can be studied using chromatography. The main interaction force in reversed‐phase liquid chromatography is the van der Waals force. The main interaction force in normal phase liquid chromatography is the Lewis acid-base interaction, including hydrogen bonding, and that in ion exchange liquid chromatography is the Coulombic force. Enantiomer separation is achieved by the combination of these molecular interaction forces with steric hindrance as the molecular recognition of proteins. Previously, the retention mechanism in reversed‐phase liquid chromatography was demonstrated using quantitative in silico analysis of chromatographic data of various compounds, such as phenolic compounds, aromatic acids, and acidic and basic drugs.1 The retention mechanism of ion exchange liquid chromatography was then quantitatively analyzed in silico. Carboxyl and guanidino phases were selected for studying the basic molecular recognition mechanism of proteins, and the selective molecular recognition of d‐amino acid oxidase was quantitatively analyzed in silico. The main molecular interaction was the Coulombic force, and the enantioselectivity was affected by the steric hindrance of the surrounding amino acid residues.

Human UGT1A6 pharmacogenetics: identification of a novel SNP, characterization of allele frequencies and functional analysis of recombinant allozymes in human liver tissue and in cultured cells.

UDP-glucuronosyltransferase (UGT) enzymes catalyze the glucuronidation and typically inactivation of endogenous and exogenous molecules including steroid hormones, bilirubin and many drugs. The UGT1A6 protein is expressed predominantly in liver and metabolizes small phenolic drugs including acetaminophen, salicylates and many beta-blockers. Interindividual variation in the capacity of humans to glucuronidate drugs has been observed. We have identified a novel common single nucleotide polymorphism (SNP) in the human UGT1A6 gene resulting in a Ser7Ala change in encoded amino acid. We have further functionally characterized that polymorphism in the context of two previously reported polymorphisms, Thr181Ala and Arg184Ser. These non-synonymous cSNPs define four common haplotypes. Alleles appear with similar frequencies in Caucasian and African-American populations with distributions adhering to Hardy-Weinberg equilibrium. UGT1A6 genotype, rate of substrate glucuronidation and level of immunoreactive UGT1A6 protein was determined. A 25-fold variation in the rate of substrate glucuronidation and an 85-fold variation in level of immunoreactive protein were measured. Liver tissue samples that were homozygous for UGT1A6*2 exhibited a high rate of glucuronidation relative to tissues with other genotypes. Biochemical kinetic studies of recombinant UGT1A6 expressed in HEK293 cells indicated that the UGT1A6*2 allozyme, expressed homozygously, had almost two-fold greater activity toward p-nitrophenol than UGT1A6*1 and when expressed heterozygously (UGT1A6*1/*2) it was associated with low enzyme activity. These data suggest that common genetic variation in human UGT1A6 confers functionally significant differences in biochemical phenotype as assessed in human tissue and cultured cells expressing recombinant allozymes. This genetic variation might impact clinical efficacy or toxicity of drugs metabolized by UGT1A6.

NEW VISUALIZING REAGENTS FOR SELECTED PHENOLIC DRUGS INVESTIGATED BY THIN LAYER CHROMATOGRAPHY

ABSTRACT Thirteen new visualizing reagents have been used to detect 13 phenolic drugs following thin layer chromatography on silica gel layers. Limits of detection (detectability), detectability index, and broadening index were determined for these drugs following use of these visualizing reagents. Aniline blue and brilliant green were the best and most universal visualizing reagents for the phenolic drugs investigated. Densitograms of selected phenolic drugs after spraying with aniline blue and brilliant green are presented.

Flow Injection Analysis of Some Phenolic Sympathomimetic Drugs

ABSTRACT A new, rapid and economical flow-injection (FI) method for deter-mining some phenolic sympathomimetic drugs is proposed. These drugs are etilefrine hydrochloride (ET), fenoterol hydrobromide (FT), hexoprenaline sulphate (HP), orciprenaline sulphate (OP) and reproterol hydrochloride (R.T). The determination is based on the reaction of the studied phenolic sympathomimetic drugs with 4-aminoantipyrine (4-AAP) and potassium hexacyanoferrate (III). The chemical reaction variables and also the FI variables, were optimized on the basis of sensitivity, sampling rate and reagent consumption. The proposed technique was applied to the analysis of pure raw materials in concentrations ranging from 2-20 μg.ml−1 in case of ET, 4-30 μg.ml−1 in case of FT and OP and from 8-50 μg.ml−1 in case of HP and RT. Samples can be introduced at rates of about 130 per hour. The suggested procedure retained its accuracy and precision when applied to the analysis of pharmaceutical dosage forms containing the corresponding drugs, as judged by the RSD (%) and students' test. The results of the analysis were found to agree statistically with those obtained by applying either the official or the referee methods. Furthermore, the validity of the results was assessed by applying the standard addition technique.

Human phenol sulfotransferases SULT1A2 and SULT1A1: Genetic polymorphisms, allozyme properties, and human liver genotype–phenotype correlations

Phenol sulfotransferases (PSTs or phenol SULTs) catalyze the sulfate conjugation of phenolic drugs, xenobiotics, and monoamines. Two human PST isoforms have been defined biochemically, a thermostable (TS), or phenol-preferring, and a thermolabile (TL), or monoamine-preferring form. Pharmacogenetic studies showed that levels of both TS PST activity and TS PST thermal stability (an indirect measure of variation in amino acid sequence) in the platelet were regulated by genetic polymorphisms. Subsequent molecular genetic experiments revealed the existence of three human PST genes, two of which, SULT1A1 and SULT1A2, encode proteins with “TS PST-like” activity. We recently reported common nucleotide polymorphisms for SULT1A1 that are associated with variations in platelet TS PST activity and thermal stability. In the present experiments, we set out to determine whether functionally significant DNA polymorphisms also might exist for SULT1A2, to compare the biochemical properties of all common allozymes encoded by SULT1A2 and SULT1A1, and to study phenol SULT genotype–phenotype correlations in the human liver. We phenotyped 61 human liver biopsy samples for TS PST thermal stability and activity. The open reading frames of SULT1A2 and SULT1A1 then were amplified with the polymerase chain reaction and sequenced for each of these hepatic tissue samples. We observed 13 SULT1A2 alleles that encoded 6 allozymes. These alleles were in linkage disequilibrium with alleles for SULT1A1. Biochemical characterization of common allozymes encoded by both genes suggested that SULT1A1 was primarily responsible for “TS PST phenotype” in the human liver. In summary, both SULT1A2 and SULT1A1 have a series of common alleles encoding enzymes that differ functionally and are associated with individual differences in phenol SULT properties in the liver.

Flow-Injection Spectrophotometric Determination of Phenolic Drugs and Carbamate Pesticides by Coupling with Diazotized 2,4,6-Trimethylaniline

A flow-injection (FI) spectrophotometric system is proposed for the determination of phenols and carbamates. In the FI manifolds, the solutions of phenols or carbamates (the latter after hydrolysis with NaOH) were injected into a diazonium ion carrier stream at pH 9.5 (buffered with tetrahydroborate), which was formed by mixing 2,4,6-trimethylaniline (TMA) with nitrate in a sodium dodecyl sulfate aqueous micellar medium. Absorbance was measured at 550 nm. The system combines the advantages derived from the use of TMA for the coupling of phenols in basic micellar media, because of the inhibition of the self-coupling reaction of the reagent, with the precision and speed of the FI procedures. Other diazotized reagents produced excessive blank signals. The procedures were successfully applied to the determination of phenolic drugs (epinephrine, acetaminophen, and gualacol) in pharmaceuticals and carbamates (bendiocarb, benfuracarb, carbaryl, carbofuran, methiocarb, promecarb, and propoxur) in pesticide products and water samples.

Recycling and redox cycling of phenolic antioxidants.

Effectiveness of phenolic antioxidants in protecting against oxidative stress depends on their reactivity towards reactive oxygen species and the reactivity of the antioxidant phenoxyl radicals towards critical biomolecules. Reduction of phenoxyl radicals by intracellular reductant (ascorbate, thiols) as well as by enzymes or intermediates of electron transport (e.g., in mitochondria and the endoplasmic reticulum) recycles phenolic antioxidants, thus enhancing antioxidant protection. Several cascades may be involved in physiologically relevant recycling of vitamin E from its phenoxyl radicals. The two major ones are dihydrolipoic acid-->(GSH)-->ascorbate, and enzymes of electron transport-->coenzyme Q. Importantly, phenoxyl radicals of vitamin E are not directly reduced by intracellular thiols. By contrast, a number of natural phenolic compounds that act as very effective scavengers of reactive oxygen species and organic radicals, may generate reactive secondary radicals of antioxidants. These secondary radicals react and modify critical intracellular targets (lipids, proteins, and DNA). As a result, the role of these phenolic compounds as biological antioxidants may be limited because of their ability to cause cyto- and genotoxic effects. Typical examples are some estrogens and phenolic drugs (e.g., the antitumor drug, etoposide) that can protect lipids but oxidize GSH and protein sulfhydryls. Moreover, phenoxyl radicals produced in the course of radical scavenging by some phenolic compounds (e.g., phenol) are capable of oxidizing both proteins and lipids. Hence, reactivity of phenoxyl radicals should be considered as a critical factor in the development of new antioxidant protectants.

Molecular biology of the human phenol sulfotransferase gene family

Cytosolic phenol sulfotransferases (PST) catalyze the sulfation/sulfonation of various phenolic agents, including catecholamines, thyroid hormones, and drugs (e.g., minoxidil and acetaminophen), which usually results in the inactivation and subsequent excretion of the compound. Our recent efforts have focused on the cloning and sequencing of the human gene family encoding the PST isozymes, and the results are summarized in this article. Multiple PST cDNA isolates have been cloned in various laboratories representing alleles of three phenol sulfotransferase gene loci termed as STP1, STP2, and STM. All three genes have been mapped precisely to a small region on human chromosome 16p12.1-p11.2 (homologous to mouse chromosome 7). The two most closely related genes, STP1 and STP2, encode isozymes of phenol-preferring PST (P-PST) and have been mapped to a single genomic cosmid clone, thus in proximity to one another. The STM gene encoding the monoamine neurotransmitter–preferring PST (M-PST) exhibits a lower level of similarity relative to STP1 and STP2. Genomic clones have been sequenced to determine the genomic organization for each of the three highly related genes. All contain seven coding exons, with conserved intron-exon boundaries. Sequencing of individual cDNA isolates from various tissues has revealed heterogeneity in the 5′ nontranslated regions, likely due to tissue-specific promoter utilization (or perhaps alternative splicing). DNA and protein polymorphisms have been identified in the population and may be useful for molecular genetic studies of the variability in the metabolism of catecholamines, thyroid hormones, and phenolic drugs, and possibly neuropsychiatric or other metabolic disorders. J. Exp. Zool. 282:223–230, 1998. © 1998 Wiley-Liss, Inc.

Molecular biology of the human phenol sulfotransferase gene family

Cytosolic phenol sulfotransferases (PST) catalyze the sulfation/sulfonation of various phenolic agents, including catecholamines, thyroid hormones, and drugs (e.g., minoxidil and acetaminophen), which usually results in the inactivation and subsequent excretion of the compound. Our recent efforts have focused on the cloning and sequencing of the human gene family encoding the PST isozymes, and the results are summarized in this article. Multiple PST cDNA isolates have been cloned in various laboratories representing alleles of three phenol sulfotransferase gene loci termed as STP1, STP2, and STM. All three genes have been mapped precisely to a small region on human chromosome 16p12.1-p11.2 (homologous to mouse chromosome 7). The two most closely related genes, STP1 and STP2, encode isozymes of phenol-preferring PST (P-PST) and have been mapped to a single genomic cosmid clone, thus in proximity to one another. The STM gene encoding the monoamine neurotransmitter-preferring PST (M-PST) exhibits a lower level of similarity relative to STP1 and STP2. Genomic clones have been sequenced to determine the genomic organization for each of the three highly related genes. All contain seven coding exons, with conserved intron-exon boundaries. Sequencing of individual cDNA isolates from various tissues has revealed heterogeneity in the 5' nontranslated regions, likely due to tissue-specific promoter utilization (or perhaps alternative splicing). DNA and protein polymorphisms have been identified in the population and may be useful for molecular genetic studies of the variability in the metabolism of catecholamines, thyroid hormones, and phenolic drugs, and possibly neuropsychiatric or other metabolic disorders.

Cloning of the human phenol sulfotransferase gene family: three genes implicated in the metabolism of catecholamines, thyroid hormones and drugs

Phenol sulfotransferases (PST) catalyze the sulfonation of catecholamines, thyroid hormones and phenolic drugs. At least two major forms of human PST enzyme have been characterized biochemically from liver, platelets and other tissues, the phenol-preferring PST (P-PST) and the monoamine neurotransmitter-preferring PST (M-PST). Molecular cloning efforts worldwide over the past 7 years have resulted in the identification of numerous PST cDNA isolates representing alleles of three human PST gene loci termed as STP1, STP2 and STM. All three genes have been mapped precisely to a small region on human chromosome 16p12.1–p11.2 (homologous to mouse chromosome 7), using somatic cell hybrids and cosmid clones. The two most closely related genes, STP1 and STP2, encoding P-PST isozymes have been mapped to a single cosmid clone and are, therefore, in close proximity to one another. STP1 and STP2 are approximately 96% identical at the amino acid sequence level, whereas, the STM gene (encoding M-PST) exhibits a lower level of identity (approximately 93–90.5%) relative to STP1 and STP2. STM is located at a distance of ca. 100 Kb from the STP1 and STP2 doublet. One may speculate that the three genes arose by gene duplication and/or gene conversion in humans. Genomic clones have been sequenced to determine the genomic organization for each of the three highly-related genes. All contain seven coding exons, with conserved intron–exon boundaries. Sequencing of individual cDNA isolates of STP1 and STM from various tissues has revealed significant heterogeneity in the 5′ nontranslated region, likely due to alternative splicing and/or tissue-specific promoter utilization. DNA polymorphisms have been detected in these genes in the human population and may be useful for molecular genetic studies of the metabolism of endogenous and xenobiotic phenolic molecules. Recent advances in the molecular biology of the human PST gene family are summarized.

BIOTRANSFORMATION IN MONKEY BRAIN: COUPLING OF SULFATION TO GLUTATHIONE CONJUGATION

Phenol sulfotransferase (PST, EC 2.8.2.1) and glutathione-S-transferase (GST, EC 2.5.1.18), the phase II biotransformation enzymes inactivate many exo- and endogenous compounds. The effect of PST substrates (catecholamines, simple phenols, selected phenolic drugs) and PST products (phenolic sulfates) on GST activity was investigated to identify possible interactions between sulfation and glutathione conjugation in the brain. Two soluble forms of PST and two forms of GST were isolated from monkey (Rhesus macacus) brain cortex. Catecholamines, hypertensive and hypotensive drugs which are sulfated by monkey brain PSTs slightly inhibit the activity of brain GSTs. The greatest inhibitory effect was observed with neurotoxic compounds such as 6-OHDA and manganese. The commonly used analgesic drugs inhibit both GST forms. These enzymes are also inhibited by phenacetin, the precursor of paracetamol, and prototype salicylates such as sodium salicylate and acetylsalicylic acid. The effect of simple phenols and their sulfated metabolites on GST activity varies. The obtained results point to a possible interaction between sulfation and glutathione conjugation in vivo since many physiologically, therapeutically and toxicologically active compounds which are sulfated by brain phenol sulfotransferases may be bound by brain glutathione-S-transferases. These compounds may lose their activity (on being bound to GST) and expose the brain to the toxic electrophiles (by decreasing GST activity).