RESUMEN
<b>Background and Objective:</b> Pineapple (<i>Ananas comosus</i>) is a popular fruit worldwide with natural antioxidant properties. This study examined how pineapple modified the expression of drug-metabolizing enzymes (CYP1A2, CYP2C9, CYP3A4, UGT1A6, NAT2 and SULT1A1) and a drug transporter (OATP1B1) in human hepatocarcinoma (HepG2) cells. <b>Materials and Methods:</b> HepG2 cells (2.5×10<sup>5</sup> cells/well in a 24-well plate) were incubated with pineapple juice extract (125-1,000 µg mL<sup>1</sup>) for 48 hrs in phenol red-free medium. Resazurin reduction, ROS, AST and ALT assays were performed. The mRNA expression of target genes was determined by RT/qPCR. <b>Results:</b> Pineapple juice slightly reduced HepG2 cell viability to 80% of the control, while ROS, AST and ALT levels were not changed. Pineapple juice did not alter the expression of CYP1A2, CYP2C9 and UGT1A6 mRNA. All tested concentrations of pineapple juice suppressed CYP3A4, NAT2 and OATP1B1 expression, while SULT1A1 expression was induced. <b>Conclusion:</b> Though pineapple juice slightly decreased the viability of HepG2 cells, cell morphology and cell function remained normal. Pineapple juice disturbed the expression of phase I (CYP3A4) and phase II (NAT2 and SULT1A1) metabolizing genes and the drug transporter OATP1B1. Therefore, the consumption of excessive amounts of pineapple juice poses a risk for drug interactions.
Asunto(s)
Ananas/metabolismo , Jugos de Frutas y Vegetales/normas , Expresión Génica/efectos de los fármacos , Células Hep G2/efectos de los fármacos , Ananas/microbiología , Arilamina N-Acetiltransferasa/efectos de los fármacos , Arilamina N-Acetiltransferasa/genética , Arilsulfotransferasa/efectos de los fármacos , Arilsulfotransferasa/genética , Citocromo P-450 CYP3A/efectos de los fármacos , Citocromo P-450 CYP3A/genética , Células Hep G2/fisiología , HumanosRESUMEN
<b>Background and Objective:</b> Dill<i> </i>(<i>Anethum graveolens</i> L.) has the potential to develop as a new alternative medicine due to its pharmacological activities. However, studies into its safety regarding herb-drug interactions have been neglected. This study investigated the risk of dill-induced herb-drug interactions (HDI) by examining its effect on the expression of phase I and II drug-metabolizing enzyme and transporter genes in Caco-2 cells. <b>Materials and Methods:</b> Caco-2 cells (5×10<sup>5</sup> cells/well) were treated with 10 µM ketoconazole, 20 µM rifampicin or dill extract (60-240 µg mL<sup>1</sup>) for 72 hrs. Cell viability was assessed using the resazurin assay and reactive oxygen species (ROS) content was determined with 2 ,7 -dichlorofluorescein diacetate. Aspartate (AST) and alanine aminotransferase (ALT) levels were measured using L-aspartate and L-alanine with α-ketoglutarate as substrate. Expression of phase I (<i>CYP1A2</i>, <i>CYP2C19</i>, <i>CYP2D6</i>, <i>CYP2E1 </i>and <i>CYP3A4</i>) and II (<i>UGT1A6</i>,<i> SULT1A1</i>,<i> NAT1</i>,<i> NAT2 </i>and<i> GSTA1/2</i>) metabolizing genes and transporters (<i>ABCB1</i>,<i> ABCC2</i>,<i> ABCG2 </i>and <i>SLCO1B1</i>) were determined by RT/qPCR. <b>Results:</b> All tested concentrations of dill did not affect cell viability or AST and ALT levels. The highest concentration of dill extract (240 µg mL<sup>1</sup>) significantly lowered the ROS level. Expression of <i>CYP1A2</i>, <i>CYP2C19</i>, <i>SULT1A1</i>, <i>NAT2 </i>and <i>ABCB1 </i>mRNA was significantly up-regulated by dill extract. <b>Conclusion:</b> Dill extract did not directly damage Caco-2 cells but prolonged use of dill may increase the risk of HDI via the up-regulation of the drug-metabolizing genes <i>CYP1A2</i>, <i>CYP2C19</i>, <i>SULT1A1</i>, <i>NAT2 </i>and the transporter <i>ABCB1</i>.
Asunto(s)
Anethum graveolens/metabolismo , Células CACO-2/efectos de los fármacos , Regulación hacia Arriba/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/efectos de los fármacos , Arilamina N-Acetiltransferasa/efectos de los fármacos , Arilsulfotransferasa/efectos de los fármacos , Citocromo P-450 CYP1A2/efectos de los fármacos , Citocromo P-450 CYP2C19/efectos de los fármacos , Interacciones de Hierba-Droga/fisiología , Humanos , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéuticoRESUMEN
Cancer is related to the cellular proliferative state. Increase in cell-cycle regulatory function augments cellular folate pool. This pathway is therapeutically targeted. A number of drugs influences this metabolism, that is, folic acid, folinic acid, nolatrexed, and methotrexate. Our previous study showed methotrexate influences on rat/human sulfotransferases. Present study explains the effect of nolatrexed (widely used in different cancers) and some micronutrients on the expressions of rat/human sulfotransferases. Female Sprague-Dawley rats were treated with nolatrexed (01-100 mg/kg) and rats of both sexes were treated to folic acid (100, 200, or 400 mg/kg) for 2-weeks and their aryl sulfotransferase-IV (AST-IV; ß-napthol sulfation) and sulfotransferase (STa; DHEA sulfation) activities, protein expression (western blot) and mRNA expression (RT-PCR) were tested. In human-cultured hepatocarcinoma (HepG2) cells nolatrexed (1 nM-1.2 mM) or folinic acid (10 nM-10 µM) were applied for 10 days. Folic acid (0-10 µM) was treated to HepG2 cells. PPST (phenol catalyzing), MPST (dopamine and monoamine), DHEAST (dehydroepiandrosterone and DHEA), and EST (estradiol sulfating) protein expressions (western-blot) were tested in HepG2 cells. Present results suggest that nolatrexed significantly increased sulfotransferases expressions in rat (protein, STa, F = 4.87, P < 0.05/mRNA, AST-IV, F = 6.702, P < 0.014; Student's t test, P < 0.01-0.05) and HepG2 cells. Folic acid increased sulfotransferases activity/protein in gender-dependant manner. Both folic and folinic acid increased several human sulfotransferases isoforms with varied level of significance (least or no increase at highest dose) in HepG2 cells pointing its dose-dependent multiphasic responses. The clinical importance of this study may be furthered in the verification of sulfation metabolism of several exogenous/endogenous molecules, drug-drug interaction and their influences on cancer pathophysiological processes. Further studies are necessary.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Micronutrientes/farmacología , Quinazolinas/farmacología , Sulfotransferasas/efectos de los fármacos , Animales , Antimetabolitos Antineoplásicos/administración & dosificación , Arilsulfotransferasa/efectos de los fármacos , Western Blotting , Ciclo Celular , Relación Dosis-Respuesta a Droga , Femenino , Ácido Fólico/administración & dosificación , Ácido Fólico/farmacología , Células Hep G2 , Humanos , Leucovorina/administración & dosificación , Leucovorina/farmacología , Masculino , Metotrexato/administración & dosificación , Metotrexato/farmacología , Micronutrientes/administración & dosificación , Quinazolinas/administración & dosificación , ARN Mensajero/biosíntesis , Ratas , Ratas Sprague-Dawley , Factores SexualesRESUMEN
Our earlier investigation showed that MTX is an inducer of rat and human sulfotransferases. Here we report that folic acid treatment inhibited MTX induction of aryl sulfotransferase (AST-IV) in female rat liver and hydroxysteroid sulfotransferase (STa) in male rat liver. This is important for understanding the clinical mechanisms of MTX.
Asunto(s)
Arilsulfotransferasa/efectos de los fármacos , Ácido Fólico/efectos de los fármacos , Metotrexato/farmacología , Sulfotransferasas/efectos de los fármacos , Animales , Antimetabolitos Antineoplásicos/farmacología , Arilsulfotransferasa/metabolismo , Interacciones Farmacológicas , Inducción Enzimática/efectos de los fármacos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Hígado/enzimología , Hígado/metabolismo , Masculino , ARN Mensajero/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Factores Sexuales , Sulfotransferasas/metabolismoRESUMEN
Sulfotransferase (SULT) 1A1 and SULT1A3 play important roles in the presystemic inactivation of beta(2) agonists in the liver and intestine, respectively. The study aimed to investigate the inhibitory effects of grapefruit juice, orange juice, green tea, black tea and oolong tea and their constituents on the activities of SULT1A1 and SULT1A3. The activities of both SULT1A1 and SULT1A3 were significantly inhibited by all the beverages investigated at a concentration of 10%. The beverage constituents were tested in concentration ranges considered to be physiologically relevant. The grapefruit constituent, quercetin, completely inhibited SULT1A1, while quercetin and naringin both partially inhibited SULT1A3. The orange constituents, tangeretin and nobiletin, also completely inhibited SULT1A1. The tea constituents, (-)-epicatechin gallate and (-)-epigallocatechin gallate, both almost completely inhibited SULT1A1 and SULT1A3. Moreover, the theaflavin and thearubigin fractions of black tea both completely inhibited SULT1A1 and strongly inhibited SULT1A3. The inhibitory action of green tea on SULT1A3 was competitive, while that of black tea and oolong tea was mixed competitive/non-competitive. Mechanism-based inhibition was not observed with any beverage. In conclusion, various beverages, especially teas, inhibit the function of SULT1A3, and therefore may have the potential to increase the bioavailability of orally administered substrates of SULT1A3, such as beta(2) agonists.
Asunto(s)
Agonistas Adrenérgicos beta/metabolismo , Arilsulfotransferasa/efectos de los fármacos , Bebidas , Sulfotransferasas/efectos de los fármacos , Arilsulfotransferasa/metabolismo , Biflavonoides/farmacología , Disponibilidad Biológica , Catequina/análogos & derivados , Catequina/farmacología , Citrus paradisi/química , Citrus sinensis/química , Flavanonas/farmacología , Flavonas/farmacología , Interacciones de Hierba-Droga , Humanos , Técnicas In Vitro , Fenoles/farmacología , Polifenoles , Quercetina/farmacología , Sulfotransferasas/metabolismo , Té/químicaRESUMEN
We have characterized hepatic phenol sulfotransferase (SULT) activities in two benthic fish species, Mullus barbatus and Lepidorhombus boscii, using p-nitrophenol, dopamine, 17beta-estradiol, 4-nonylphenol, and 1-naphthol as substrates. High affinity sulfation of 17beta-estradiol was observed in both species (Km=28-75 nM), suggesting the presence of a specific estrogen sulfotransferase that catalyzes the formation of estradiol-3 sulfate. Among the tested compounds, 1-naphthol was the most effective substrate for sulfation, with Vmax/Km ratios several hundred-fold higher than the other substrates examined. Both species sulfated the tested compounds, but only M. barbatus was able to sulfate dopamine. We also tested the inhibitory effects of common marine pollutants with estrogenic (4-nonylphenol) and androgenic (tributyltin, triphenyltin) properties on p-nitrophenol and 17beta-estradiol SULT activities. 4-Nonylphenol and triphenyltin inhibited sulfation of both substrates at micromolar concentrations in both species. However, tributyltin was only effective against SULTs from L. boscii, again at micromolar concentrations. The data indicate that M. barbatus and L. boscii are able to sulfate a range of xenobiotics and endogenous compounds, and inhibition of these activities by environmental pollutants may contribute to the known toxic effects of these compounds.
Asunto(s)
Arilsulfotransferasa/efectos de los fármacos , Disruptores Endocrinos/toxicidad , Peces Planos/metabolismo , Perciformes/metabolismo , Contaminantes Químicos del Agua/toxicidad , Animales , Arilsulfotransferasa/metabolismo , Dopamina/metabolismo , Estradiol/análogos & derivados , Estradiol/química , Estradiol/metabolismo , Femenino , Concentración 50 Inhibidora , Hígado/enzimología , Masculino , Nitrofenoles/metabolismo , Compuestos Orgánicos de Estaño/toxicidad , Fenoles/metabolismo , Fenoles/toxicidad , Compuestos de Trialquiltina/toxicidadRESUMEN
Polychlorinated biphenyls (PCBs) can be metabolized by cytochromes P450 to hydroxylated biotransformation products. In mammalian studies, some of the hydroxylated products have been shown to be strong inhibitors of steroid sulfotransferases. As a part of ongoing research into the bioavailability of environmental pollutants in catfish intestine, we investigated the effects of a series of hydroxylated PCBs (OH-PCBs) on two conjugating enzymes, phenol-type sulfotransferase and glucuronosyltransferase. We incubated cytosolic and microsomal samples prepared from intestinal mucosa with 3-hydroxy-benzo[a]pyrene and appropriate cosubstrates and measured the effect of OH-PCBs on the formation of BaP-3-glucuronide and BaP-3-sulfate. We used PCBs with 4, 5, and 6 chlorine substitutions and the phenolic group in the ortho, meta, and para positions. OH-PCBs with the phenolic group in the ortho position were weak inhibitors of sulfotransferase; the median inhibitory concentration (IC50) ranged from 330 to 526 microM. When the phenol group was in the meta or para position, the IC50 was much lower (17.8-44.3 microM). The OH-PCBs were more potent inhibitors of glucuronosyltransferase, with IC50s ranging from 1.2 to 36.4 microM. The position of the phenolic group was not related to the inhibitory potency: the two weakest inhibitors of sulfotransferase, with the phenolic group in the ortho position, were 100 times more potent as inhibitors of glucuronosyltransferase. Inhibition of glucuronosyltransferase by low concentrations of OH-PCBs has not been reported before and may have important consequences for the bioavailability, bioaccumulation, and toxicity of other phenolic environmental contaminants.
Asunto(s)
Arilsulfotransferasa/metabolismo , Benzopirenos/metabolismo , Contaminantes Ambientales/efectos adversos , Glucuronosiltransferasa/metabolismo , Bifenilos Policlorados/efectos adversos , Animales , Arilsulfotransferasa/efectos de los fármacos , Disponibilidad Biológica , Biotransformación , Bagres/fisiología , Sistema Digestivo/enzimología , Relación Dosis-Respuesta a Droga , Contaminantes Ambientales/farmacocinética , Femenino , Glucuronosiltransferasa/efectos de los fármacos , Hidroxilación , Masculino , Bifenilos Policlorados/farmacocinéticaRESUMEN
Human monoamine (M)-form and simple phenol (P)-form phenol sulfotransferases (PSTs), which are greater than 93% identical in their primary sequences, were used as models for investigating the structural determinants responsible for their distinct substrate specificity and other enzymatic properties. A series of chimeric PSTs were constructed by reciprocal exchanges of DNA segments between cDNAs encoding M-form and P-form PSTs. Functional characterization of the recombinant wild-type M-form, P-form, and chimeric PSTs expressed in Escherichia coli and purified to homogeneity revealed that internal domain-spanning amino acid residues 84-148 contain the structural determinants for the substrate specificity of either M-form or P-form PST. Data on the kinetic constants (Km, Vmax, and Vmax/Km) further showed the differential roles of the two highly variable regions (Region I spanning amino acid residues 84-89 and Region II spanning amino acid residues 143-148) in substrate binding, catalysis, and sensitivity to the inhibition by 2,6-dichloro-4-nitrophenol. In contrast to the differential sulfotransferase activities of M-form and P-form PSTs toward dopamine and p-nitrophenol, the Dopa/tyrosine sulfotransferase activities were found to be restricted to M-form, but not P-form, PST. Furthermore, the variable Region II of M-form PST appeared to play a predominant role in determining the Dopa/tyrosine sulfotransferase activities of chimeric PSTs. Kinetic studies indicated the role of manganese ions in dramatically enhancing the binding of D-p-tyrosine to wild-type M-form PST. Taken together, these results pinpoint unequivocally the sequence encompassing amino acid residues 84-148 to be the substrate specificity/catalytic domain of both M-form and P-form PSTs and indicate the importance of the variable Regions I and II in determining their distinct enzymatic properties.
Asunto(s)
Arilsulfotransferasa/metabolismo , Secuencia de Aminoácidos , Arilsulfotransferasa/efectos de los fármacos , Arilsulfotransferasa/genética , Arilsulfotransferasa/aislamiento & purificación , Sitios de Unión , Dopamina/metabolismo , Escherichia coli/genética , Humanos , Cinética , Manganeso/farmacología , Datos de Secuencia Molecular , Nitrofenoles/metabolismo , Nitrofenoles/farmacología , Proteínas Recombinantes de Fusión/metabolismo , Homología de Secuencia de Aminoácido , Especificidad por SustratoRESUMEN
1. Hepatic drug metabolism was investigated in normal, adjuvant-induced arthritic (AA), indomethacin-treated AA and prednisolone-treated AA rats. The contents of P450 and b5 and the activities of NADH-b5 reductase (fp2), NADPH-ferrihaemoprotein reductase, P450 mixed function oxidase, FAD-monooxygenase and several enzymes involved in conjugation were remarkably lower in AA than in normal rats. 2. Many of the decreased enzyme activities were restored to normal levels by the continuous administration (3 weeks) of indomethacin or prednisolone, which improved the arthritic states of the animals. However, the restoration of FAD-monooxygenase activity by the administration of indomethacin or prednisolone was incomplete. The P450 and b5 contents and the fp2 activity in prednisolone-treated AA rats were also significantly lower than those in normal rats. 3. These findings indicate that the ability of the liver to metabolize drugs (both oxidation and conjugation) in AA rats is greatly decreased and that a long series of the treatment of AA rats with anti-inflammatory drugs is required to restore several enzyme activities.
Asunto(s)
Artritis Experimental/enzimología , Hígado/enzimología , Preparaciones Farmacéuticas/metabolismo , Animales , Artritis Experimental/tratamiento farmacológico , Arilsulfotransferasa/efectos de los fármacos , Arilsulfotransferasa/metabolismo , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Sistema Enzimático del Citocromo P-450/metabolismo , Reductasas del Citocromo/efectos de los fármacos , Reductasas del Citocromo/metabolismo , Citocromo-B(5) Reductasa , Glutatión Transferasa/efectos de los fármacos , Glutatión Transferasa/metabolismo , Indometacina/farmacología , Hígado/efectos de los fármacos , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Oxigenasas de Función Mixta/efectos de los fármacos , Oxigenasas de Función Mixta/metabolismo , NADPH-Ferrihemoproteína Reductasa/efectos de los fármacos , NADPH-Ferrihemoproteína Reductasa/metabolismo , Oxigenasas/efectos de los fármacos , Oxigenasas/metabolismo , Prednisolona/farmacología , Ratas , Ratas WistarRESUMEN
Sulfate conjugates are a heterogeneous class of polar, anionic metabolites that result from the conjugation of endogenous and exogenous compounds. Sulfate conjugates exhibit a high degree of binding to albumin, the extent of which usually exceeds those of their parent compounds. Preponderant direct and indirect evidence suggests that sulfation activity is slightly higher in the periportal than in the perivenous (centrilobular) region of the liver, but recent immunohistochemical studies imply that specific isoforms of the sulfotransferases may also be preferentially localized in the perivenous region. Entry of sulfate conjugates into the liver cell is poor unless discrete carriers are present. Although known transport carriers exist for the sulfated bile acids, the specificity of the carriers for drug sulfate conjugates is presently unknown. The removal of sulfates is usually by way of biliary excretion while, on occasion, sulfates can be desulfated and participate in futile cycling with their parent compounds. The binding, transport, and hepatic elimination of various drug sulfate conjugates are examined. Non-recirculating studies carried out in the perfused rat liver with the multiple indicator dilution technique under varying input sulfate conjugate concentrations have provided essential information on the effects of vascular (red blood cells and plasma protein) binding on transport and removal of the conjugates. These studies clearly demonstrate the need to study protein binding, transmembrane transfer characteristics across the liver basolateral (sinusoidal) and canalicular membranes, and enzyme zonation in a distributed-in-space fashion in order to properly define the handling of sulfate conjugates in the liver.
Asunto(s)
Bilis/metabolismo , Hígado/metabolismo , Sulfatos/metabolismo , Animales , Arilsulfotransferasa/efectos de los fármacos , Arilsulfotransferasa/metabolismo , Hígado/citología , Unión Proteica , Ratas , Albúmina Sérica/metabolismo , Distribución TisularRESUMEN
Enzymatic and immunohistochemical experiments were conducted to evaluate the mechanistic basis for the downregulation of the important detoxication/bioactivation enzyme aryl sulfotransferase IV (AST IV) during 2-acetylaminofluorene (2AAF)-induced hepatocarcinogenesis. To distinguish between possible genotoxic and cytotoxic actions of 2AAF, three different dietary protocols were used in these experiments: group 1 received 2AAF for 12 wk, group 2 received 2AAF for 3 or 6 wk and then a control diet lacking xenobiotics for 3 or 6 wk, and group 3 received 2AAF for 3 or 6 wk and then phenobarbital for 3 or 6 wk. When hepatic AST IV activity was assessed, N-hydroxy-2AAF sulfotransferase activity was found to decrease 80-90% in response to 2AAF feeding, but activity recovered to essentially normal levels in the livers of rats subsequently placed on either control diets or diets with phenobarbital, suggesting a reversible cytotoxic mechanism for loss of AST IV activity. However, when liver sections from the rats were evaluated immunohistochemically, two distinct patterns were detected for the downregulation of AST IV activity. In the livers of rats administered only 2AAF (group 1), a general pattern of overall downregulation of AST IV expression was observed throughout the liver and among most but not all newly developed nodules. In tissue sections from rats initially fed 2AAF and then placed on a control diet (group 2) or a diet with phenobarbital (group 3), the nodules continued to show low levels of AST IV expression, while expression in the areas surrounding nodules returned to the normal, high levels. In addition, among those rats fed 2AAF for just 3 wk and then control diet or diet containing phenobarbital for 6 wk, only rats fed phenobarbital developed altered foci that stained weakly for AST IV expression. These results show that there were two kinds of 2AAF-mediated decrease in hepatic AST IV activity: a general overall loss of AST IV expression dependent on administration of 2AAF and reversible upon removal of 2AAF from the diet and a loss of AST IV expression among newly developed liver foci and nodules that persisted in the absence of 2AAF administration and appeared to be a property of 2AAF-induced subpopulations of cells. These patterns may correspond, respectively, to cytotoxic and genotoxic mechanisms of 2AAF action.
Asunto(s)
2-Acetilaminofluoreno/toxicidad , Arilsulfotransferasa/efectos de los fármacos , Arilsulfotransferasa/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Isoenzimas/efectos de los fármacos , Isoenzimas/metabolismo , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/enzimología , Hígado/efectos de los fármacos , Hígado/enzimología , Animales , Citosol/enzimología , Hidroxiacetilamino Fluoreno/metabolismo , Inmunohistoquímica , Masculino , Fenobarbital/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
The sulphate conjugation of serotonin and N-acetylserotonin (NAS) was studied in the mosquito, Aedes togoi, using a high-pressure liquid chromatography-radioisotopic procedure. This involved the transfer of the sulphate group from 3'-phosphoadenosine-5'-phosphosulphate (PAP35S) to serotonin or NAS by phenolsulphotransferase (PST). NAS, the acetylated product, is less polar than serotonin but it is a better substrate of PST. Its removal would conceivably be facilitated by sulphate conjugation which renders it more water-soluble. This sequential two-step reaction, comprising N-acetylation of serotonin and sulphate conjugation of the acetylated product (NAS) was also demonstrated in vitro. The developmental profile of PST activity using NAS as substrate showed that peak activity occurred at pupation and increased progressively for a few days after emergence of the adult. Based on the selective inhibition of the "P" form of PST by 2,6-dichloro-4-nitrophenol (DCNP), the sulphate conjugation of NAS appeared to be catalysed by the "M" form of PST.
Asunto(s)
Aedes/metabolismo , Serotonina/análogos & derivados , Serotonina/metabolismo , Sulfatos/metabolismo , Aedes/enzimología , Animales , Arilsulfotransferasa/efectos de los fármacos , Arilsulfotransferasa/metabolismo , Hidrólisis , Nitrofenoles/farmacología , Fosfoadenosina Fosfosulfato/metabolismoRESUMEN
This study characterized the effects of liver damage produced by a variety of hepatotoxicants on several components of the sulfation pathway in rats. Specifically, the concentration of cosubstrate, adenosine 3'-phosphate 5'-phosphosulfate (PAPS), and the hepatic capacity for PAPS synthesis were measured in livers of rats treated with carbon tetrachloride (CCl4), 1,1-dichloroethylene (DCE), alpha-naphthylisothiocyanate (ANIT), aflatoxin B1 (ATX), allyl alcohol (AA), bromobenzene (BB), cadmium chloride (Cd), or thioacetamide (TA). Liver damage was assessed by measuring serum sorbitol dehydrogenase (SDH) and alanine aminotransferase (ALT) activities as well as by histopathological examination. Hepatic PAPS concentration was generally decreased as a result of treatment with hepatotoxicants (35-80% of control), although BB, AA, and ANIT were without effect. Maximal hepatic capacity for PAPS synthesis, determined as the activities of PAPS synthetic enzymes, ATP sulfurylase, and APS kinase, was selectively decreased by the hepatotoxicants. ATP sulfurylase activity was decreased by Cd and TA (55 and 62% of control, respectively), whereas APS kinase activity was decreased by Cd, TA, BB, and DCE (60-77% of control, respectively). In addition, phenol sulfotransferase (PST) activity was measured toward 1- and 2-naphthol in order to determine whether apparent changes in PST activity in damaged livers are substrate-dependent. Treatment with hepatotoxicants generally decreased 1-naphthol-directed PST activity but not PST activity directed toward 2-naphthol. In conclusion, (1) not all xenobiotic-induced liver injury results in decreased hepatic PAPS concentration, (2) some hepatotoxicants decrease PAPS concentration by a mechanism other than decreased cosubstrate synthesis, and (3) the effect of hepatotoxicants on PST activity is dependent upon the choice of substrate used in the enzymatic assay.