Human liver budesonide sulphotransferase is inhibited by testosterone and correlates with by testosterone sulphotransferase

Pacifici, Gian Maria; Ferroni, M. A.; Temellini, A.; Gucci, A.; Morelli, Maria Cristina; Giuliani, L.

doi:10.1007/bf00195915

Cited by 11 publications

(9 citation statements)

References 31 publications

(21 reference statements)

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“…Little is known about glucuronosyltransferase interindividual variability and the present results and those on ethinyloestradiol (3) and zidovudine (8) are consistent with the view that glucuronosyltransferase activity is positively skewed and varies over 20-fold. Whether the glucuronosyltransferase distribution pattern is, or is not, bimodal is still open to question.…”

Section: Assayssupporting

confidence: 76%

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Testosterone sulphation and glucuronidation in the human liver: interindividual variability

Pacifici

Gucci

Giuliani

1997

European Journal of Drug Metabolism and Pharmacokinetics

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Presystemic sulphation and glucuronidation at OH-C17 limits the bioavailability of testosterone; the aim of this investigation was to describe the variability in testosterone sulphation and glucuronidation rates in the human liver. Liver samples were obtained from 61 women and 40 men of similar age (mean 53 and 55 years, respectively) submitted to surgery. The mean rate of testosterone sulphation was significantly (P = 0.002) higher in men (22.4 pmol/min/mg) than in women (17.5 pmol/min/mg), was not age-dependent, followed bimodal distribution and varied over 7-fold in men and women. There was a weak, but significant negative correlation (r = -0.380; P = 0.003), between the rate of testosterone glucuronidation and age in the liver of women but not in that of men. The mean rate (pmol/min/mg) of testosterone glucuronidation was 155 (men) and 105 (women) (NS) and varied over 20-fold. When the rate of testosterone glucuronidation was expressed on the basis of g liver equivalent, the mean estimates were significantly (P = 0.003) greater in men (3323 pmol/min/g) than in women (1841 pmol/min/g). The present findings are consistent with the view that the hepatic activities of sulphotransferase and glucuronosyltransferase are higher in men than in women and that they vary in the human liver.

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Section: Assayssupporting

confidence: 76%

“…Preliminary. results on the sulphation of testosterone have shown that testosterone sulphotransferase activity is higher in men than in women (8) and the first aim of this study was to examine in detail the variability in the human liver testosterone sulphotransferase activity.…”

Section: Introductionmentioning

confidence: 99%

Testosterone sulphation and glucuronidation in the human liver: interindividual variability

Pacifici

Gucci

Giuliani

1997

European Journal of Drug Metabolism and Pharmacokinetics

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“…DHEA-ST is capable of conjugating both the 3␣-and 3␤-hydroxyls of hydroxysteroids, the 3-phenolic hydroxyl of estrogens, as well as the 17␤-hydroxyl of testosterone and ␤-estradiol (Falany et al, 1989). This observation is consistent with the report of Pacifici et al (1994) that human liver budesonide sulfation was inhibited by testosterone and correlated with testosterone sulfotransferase activity. To date, DHEA-ST is the only human SULT reported to sulfate testosterone.…”

Section: Discussionsupporting

confidence: 82%

“…This mechanism is thought to prolong the duration of the pharmacological effects of budesonide in the lung (Tunek et al, 1997). Another report (Pacifici et al, 1994) has shown that budesonide can be conjugated with sulfate in human liver and to some extent in lung, but the site of conjugation in the molecule, as well as the sulfotransferase (SULT 1 ) isoenzymes involved, is not known. Of particular interest in this study is the ability of human cytosolic SULTs to catalyze the sulfate conjugation of the budesonide epimers.…”

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confidence: 99%

Sulfation of Budesonide by Human Cytosolic Sulfotransferase, Dehydroepiandrosterone-Sulfotransferase (DHEA-ST)

Meloche

Sharma²,

Swedmark³

et al. 2002

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Budesonide, a synthetic glucocorticosteroid, is used in the treatment of asthma and allergic reactions, rhinitis, and inflammatory bowel disease. It is distributed as a mixture of two epimers, 22R and 22S, and has a high ratio of topical to systemic activity due to extensive first-pass metabolism to metabolites with minimal activity. Previous studies have shown that the epimers are metabolized by the cytochrome P450 monooxygenase system. Metabolism and inactivation of the epimers by the phase II enzymes has not been well characterized. This study describes the conjugation of budesonide by human cytosolic sulfotransferases (SULTs). Seven human SULTs were analyzed to determine which were capable of catalyzing the sulfation of the epimers of budesonide. Only dehydroepiandrosterone-sulfotransferase (DHEA-ST, SULT2A1) was capable of forming a sulfated budesonide product. The epimeric forms of budesonide display different kinetic activities with the 22R epimer having a 3.5-fold greater rate of sulfation activity than the 22S epimer. The structure of budesonide shows two hydroxyl sites that are potential sites for sulfate conjugation, but analysis by mass spectrometry indicates the formation of only a monosulfated budesonide product. A modeling approach was used to define the site of sulfation as that of the 21-hydroxyl group. Although sulfation of budesonide by DHEA-ST may not be an important factor in its use as an antiasthmatic, intestinal and hepatic sulfation will be important for its proposed systemic use as an anti-inflammatory agent.Budesonide (Fig. 1) is a synthetic glucocorticosteroid used in the treatment of asthma, rhinitis, and inflammatory bowel diseases. It has a high ratio of topical to systemic activity partly due to extensive first-pass metabolism in the liver to metabolites with minimal activity (Clissold and Heel, 1984). Budesonide is distributed as a mixture of two epimers, 22R and 22S. The epimeric mixture is a 1:1 ratio whereby the 22R epimer has been reported to have a potency that is 2-to 3-fold greater than the 22S epimer based on topical activity (Brattsand et al., 1982).Previous in vitro studies with human liver microsomes have demonstrated that the budesonide epimers are differentially metabolized by the cytochrome P450 monooxygenase system. Budesonide 22R is metabolized by CYP3A4 to two major metabolites, 16␣-hydroxyprednisolone and 6␤-hydroxybudesonide, whereas the 22S epimer is only metabolized to one major metabolite, 6␤-hydroxybudesonide (Jonsson et al., 1995). These metabolites are also present in high amounts in plasma and urine after administration of budesonide to humans (P. Anderson, AstraZeneca, unpublished results). In contrast to phase I metabolism, only limited information on the metabolism of budesonide by the phase II drug-metabolizing enzymes is available.

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“…It seems more likely that the reason behind both the higher levels found in our asthmatic patients and the subsequent changes after budesonide treatment are the result of enzymatic events. Metabolism of budesonide as well as salbutamol is dependent on enzymes within the sulfotransferases family (Pacifici et al 1994). Enzymatic induction at this level might be a possible explanation for the changes found in salbutamolplasma levels after budesonide.…”

Section: Discussionmentioning

confidence: 99%

Metabolism of Salbutamol Differs between Asthmatic Patients and Healthy Volunteers

Sjöswärd¹,

Josefsson²,

Ahlner³

et al. 2003

Pharmacology & Toxicology

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Patients with asthma are a target group for medication with b2-agonists, often in combination with corticosteroids. Salbutamol is commonly marketed as racemate. R-Salbutamol carries b2-agonistic property whereas S-salbutamol does not. The racemate undergoes stereoselective sulphatisation by sulfotransferases mainly in the gut and liver, so that S-salbutamol rests for a longer time in the body and reaches higher plasma levels than R-salbutamol. Ten patients with mild stable asthma and at present without cortisone medication were given racemic salbutamol as ventoline 4 mg orally. Plasma and urine levels were estimated until 24 hr after ingestion. For comparison healthy volunteers were treated in the same way.The group of asthma patients was then treated with budesonide inhalations 800 mg daily for one week and the initial programme resumed. Non-cortisone-treated asthmatic patients displayed higher levels of both R-and S-salbutamol in plasma than did healthy volunteers after one single ingestion of racemic salbutamol (CMAX both comparisons PϽ0.05). Plasma levels of salbutamol isomers in cortisone-treated asthmatic patients resembled the levels in volunteers. The most plausible explanation for the discrepancy in values between asthmatic patients and volunteers is a defective metabolic function by asthmatic patients possibly enzymatic in origin.Racemic R,S salbutamol is used to relieve bronchial constriction, the b2-agonist effect being mediated by the Renantiomer. S-Salbutamol may also have a pharmacological effect, but distinctly different from that of R-salbutamol. In vitro experiments have indicated increased production of histamine in mast cells following S-salbutamol (Cho et al. 2001) and furthermore, increase of intracellular Ca 2π by muscarinic receptor activation has been shown in connection with the S-enantiomer (Mitra et al. 1998). The latter effect may be a possible link to enhanced bronchial hyperresponsiveness, suggested to occur after regular treatment with salbutamol in asthmatic patients, and suspected to be associated with the presence of S-salbutamol (Nelson 1999).Previous studies have shown a distinct stereoselective metabolism. Both R-and S-enantiomers are metabolised by sulfotransferases, mainly in the gut and liver (Walle et al. 1996);(Hartman et al. 1998) to inactive metabolites. Sulfotransferases work more effectively with the R-enantiomer, hence the bioavailability of S-isomer by far exceeds that of the R-enantiomer, resulting in S-to R-salbutamol ratio in plasma exceeding one after administration to human beings. Racemisation in the stomach accounts for a small degree (6%) of interconversion (Boulton & Fawcett 2001).Although a limited number of pharmacokinetic studies has been performed in asthmatic patients, most pharmacokinetic studies have been conducted on healthy volunteers. It seems more appropriate though, to study a target popula-

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Human liver budesonide sulphotransferase is inhibited by testosterone and correlates with by testosterone sulphotransferase

Cited by 11 publications

References 31 publications

Testosterone sulphation and glucuronidation in the human liver: interindividual variability

Testosterone sulphation and glucuronidation in the human liver: interindividual variability

Sulfation of Budesonide by Human Cytosolic Sulfotransferase, Dehydroepiandrosterone-Sulfotransferase (DHEA-ST)

Metabolism of Salbutamol Differs between Asthmatic Patients and Healthy Volunteers

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