Enzymatic and non-enzymatic sulfation mechanisms in the biological actions of minoxidil

Meisheri, Kaushik D.; Johnson, George; Puddington, Lynn

doi:10.1016/0006-2952(93)90061-z

Cited by 53 publications

(19 citation statements)

References 25 publications

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“…Most sulfate and glucuronide metabolites are inactive; notable exceptions include morphine-6-glucuronide, minoxidil sulfate, SN-38-glucuronide, and troglitazone sulfate (Zamek-Gliszczynski et al, 2006b). Altered hepatic export of pharmacologically and toxicologically active sulfate and glucuronide metabolites formed in the liver can have profound pharmacodynamic and toxic implications, underscoring the importance of understanding the mechanisms of metabolite excretion (Meisheri et al, 1993;Funk et al, 2001;Horikawa et al, 2002;. Despite the importance of active transport in hepatic excretion of phase II metabolites, mechanisms responsible for excretion of sulfate and glucuronide conjugates have not been elucidated fully.…”

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confidence: 99%

The Important Role of Bcrp (Abcg2) in the Biliary Excretion of Sulfate and Glucuronide Metabolites of Acetaminophen, 4-Methylumbelliferone, and Harmol in Mice

Zamek‐Gliszczynski¹,

Nezasa²,

Tian³

et al. 2006

Mol Pharmacol

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The role of Mrp2, Bcrp, and P-glycoprotein in the biliary excretion of acetaminophen sulfate (AS) and glucuronide (AG), 4-methylumbelliferyl sulfate (4MUS) and glucuronide (4MUG), and harmol sulfate (HS) and glucuronide (HG) was studied in Abcc2(Ϫ/Ϫ), Abcg2(Ϫ/Ϫ), and Abcb1a(Ϫ/Ϫ)/Abcb1b(Ϫ/Ϫ) mouse livers perfused with the respective parent compounds using a cassette dosing approach. Biliary clearance of the sulfate conjugates was significantly decreased in Bcrp-deficient mouse livers, resulting in negligible biliary excretion of AS, 4MUS, and HS. It is noteworthy that the most profound decrease in the biliary clearance of the glucuronide conjugates was observed in Bcrp-deficient mouse livers, although the biliary clearance of 4MUG was also ϳ35% lower in Mrp2-deficient mouse livers. As expected, biliary excretion of conjugates was not impaired in P-glycoprotein-deficient livers. An appreciable increase in perfusate recovery due to a shift in the directionality of metabolite excretion, from bile to perfusate, was noted in knockout mice only for conjugates whose biliary clearance constituted an appreciable (Ն37%) fraction of total hepatic excretory clearance (i.e., 4MUS, HG, and HS). Biliary clearance of AG, AS, and 4MUG constituted a small fraction of total hepatic excretory clearance, so an appreciable increase in perfusate recovery of these metabolites was not observed in knockout mice despite markedly decreased biliary excretion. Unlike in rats, where sulfate and glucuronide conjugates were excreted into bile predominantly by Mrp2, mouse Bcrp mediated the biliary excretion of sulfate metabolites and also played a major role in the biliary excretion of the glucuronide metabolites, with some minor contribution from mouse Mrp2.Phase II metabolism, including sulfation and glucuronidation, occurs primarily in the liver. Conjugation of a substrate with a sulfate or glucuronide moiety increases its hydrophilicity to promote excretion from the body. These conjugates are typically too polar to undergo passive diffusion from hepatocytes after their intracellular formation and therefore require carrier-mediated transport for excretion across the hepatic canalicular (apical) membrane into bile and across the basolateral membrane into sinusoidal blood. Most sulfate and glucuronide metabolites are inactive; notable exceptions include morphine-6-glucuronide, minoxidil sulfate, SN-38-glucuronide, and troglitazone sulfate (Zamek-Gliszczynski et al., 2006b). Altered hepatic export of pharmacologically and toxicologically active sulfate and glucuronide metabolites formed in the liver can have profound pharmacodynamic and toxic implications, underscoring the importance of understanding the mechanisms of metabolite excretion (Meisheri et al., 1993;Funk et al., 2001;Horikawa et al., 2002;. Despite the importance of active transport in hepatic excretion of phase II metabolites, mechanisms responsible for excretion of sulfate and glucuronide conjugates have not been elucidated fully.

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mentioning

confidence: 99%

The Important Role of Bcrp (Abcg2) in the Biliary Excretion of Sulfate and Glucuronide Metabolites of Acetaminophen, 4-Methylumbelliferone, and Harmol in Mice

Zamek‐Gliszczynski¹,

Nezasa²,

Tian³

et al. 2006

Mol Pharmacol

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“…However, in the case of mutagenic and carcinogenic N-hydroxyarylamines and heterocyclic amines and benzylic alcohols of polycyclic aromatic hydrocarbons, sulfonation is a critical step in their metabolic activation to electrophiles that can bind tissue macromolecules such as DNA (3)(4)(5)(6). Further, sulfonation has been shown to activate the antihypertensive and hair growth stimulant minoxidil (7). The overall role that sulfonation plays in disease states such as neurodegeneration and cancer is currently under active investigation (8 -10).…”

mentioning

confidence: 99%

The Structure of Human SULT1A1 Crystallized with Estradiol

Gamage

Tsvetanov

Duggleby

et al. 2005

Journal of Biological Chemistry

106

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Human SULT1A1 belongs to the supergene family of sulfotransferases (SULTs) involved in the sulfonation of xeno-and endobiotics. The enzyme is also one of the SULTs responsible for metabolic activation of mutagenic and carcinogenic compounds and therefore is implicated in various cancer forms. Further, it is not well understood how substrate inhibition takes place with rigid fused multiring substrates such as 17␤-estradiol (E2) at high substrate concentrations when subcellular fractions or recombinant enzymes are used. To investigate how estradiol binds to SULT1A1, we co-crystallized SULT1A1 with sulfated estradiol and the cofactor product, PAP (3-phosphoadenosine 5-phosphate). The crystal structure of SULT1A1 that we present here has PAP and one molecule of E2 bound in a nonproductive mode in the active site. The structure reveals how the SULT1A1 binding site undergoes conformational changes to accept fused ring substrates such as steroids. In agreement with previous reports, the enzyme shows partial substrate inhibition at high concentrations of E2. A model to explain these kinetics is developed based on the formation of an enzyme⅐PAP⅐E2 dead-end complex during catalysis. This model provides a very good quantitative description of the rate versus the [E2] curve. This dead-end complex is proposed to be that described by the observed structure, where E2 is bound in a nonproductive mode. Cytosolic sulfotransferases (SULTs)2 are involved in the phase II metabolism of numerous xeno-and endobiotics such as drugs, neurotransmitters, bile acids, and hormones (1, 2). SULTs utilize the cofactor 3Ј-phosphoadenosine 5Ј-phosphosulfate (PAPS) as the sulfonate (SO 3 Ϫ1 ) donor in such reactions that generally lead to the detoxification of substrates by making them more water-soluble and thereby readily excretable via the kidneys. However, in the case of mutagenic and carcinogenic N-hydroxyarylamines and heterocyclic amines and benzylic alcohols of polycyclic aromatic hydrocarbons, sulfonation is a critical step in their metabolic activation to electrophiles that can bind tissue macromolecules such as DNA (3-6). Further, sulfonation has been shown to activate the antihypertensive and hair growth stimulant minoxidil (7). The overall role that sulfonation plays in disease states such as neurodegeneration and cancer is currently under active investigation (8 -10). SULT1A1 has a broad tissue distribution and has been shown to metabolize a wide range of xenobiotics and play a significant role in the metabolism of estrogens and iodothyronines. In resolving the crystal structure (11) of SULT1A1 we showed that it contains a very hydrophobic L-shaped substrate-binding region, which explains how it can accommodate small planar compounds as well as larger L-shaped aromatics such as iodothyronines. However, in those studies we could not explain how extended fused ring systems, such as 17␤-estradiol (E2), can act as substrates of SULT1A1. In addition, no real information has been provided as to why the metabolism of E2 is inhibited at high...

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“…These observations, which are in contrast to the results obtained with classical K ATP channel openers, have mostly been interpreted as reflecting a negative allosteric coupling of the binding sites for P1075 and minoxidil sulphate or heterogeneity of the otherwise homogeneous opener sites (Hambrock et al 1998;Schwanstecher et al 1998). Alternatively, minoxidil sulphate, which is known to sulphate proteins easily at the N-terminus and at histidine residues (Meisheri et al 1993b), could transfer its sulphate group to a histidine at or near the opener binding site, thereby inhibiting further binding of the drug.…”

Section: Introductionmentioning

confidence: 77%

Atypical effect of minoxidil sulphate on guinea pig airways

Buchheit

Hofmann

Manley

et al. 2000

Naunyn-Schmiedeberg's Archives of Pharmacology

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The effects of minoxidil sulphate, an "atypical" K(ATP) channel opener, and bimakalim, a benzopyran-type classical K(ATP) channel opener, on guinea pig airways in vitro and in vivo and on isolated portal veins from rats and guinea pigs were compared. Minoxidil sulphate inhibited the spontaneous activity of isolated guinea pig and rat portal vein preparations with pD2 values of 7.83+/-0.08 and 7.14+/-0.03, respectively (Emax=100% in both preparations). Bimakalim caused a more potent inhibition with pD2 values of 8.80+/-0.05 and 8.20+/-0.04, respectively (Emax=100% in both preparations). Minoxidil sulphate reduced the spontaneous tone of isolated guinea pig tracheal rings with a pIC50 value of 3.92+/-0.02 and the same efficacy as isoprenaline. Bimakalim was more potent (pIC50=7.25+/-0.02) but less efficacious (Emax=75% of the Emax of isoprenaline). The airway relaxant effect of bimakalim, but not minoxidil sulphate, was antagonised by glibenclamide (pA2=7.50) at concentrations above 0.1 microM. Bombesin-induced bronchoconstriction in anaesthetised, ventilated, normoreactive guinea pigs (measured as increase in total lung resistance) was dose-dependently reversed by intratracheally (i.t.) administered bimakalim (ED50=4 microg/kg; Emax=92% of maximally possible inhibition), but not by minoxidil sulphate, at doses up to 1 mg/kg i.t. In the same animals, following i.t. administration of higher doses, both minoxidil sulphate and bimakalim reduced blood pressure. Airways hyperreactivity to histamine induced by acute treatment of guinea pigs with immune complex was dose-dependently reversed by bimakalim (ED50=0.5 microg/kg i.t., Emax=100%). This effect was antagonised by glibenclamide (30 mg/kg i.v.). Minoxidil sulphate had a biphasic effect on airways hyperreactivity: at 1 microg/kg i.t., airways hyperreactivity was augmented, whereas at doses above 3.2 microg/kg i.t. it caused reversal of airways hyperreactivity. Both of the effects of minoxidil sulphate were insensitive to glibenclamide (30 mg/kg i.v.). It is concluded that the pharmacological profile of minoxidil sulphate in guinea pig airways is completely different from that of classical K(ATP) channel openers such as bimakalim. Minoxidil sulphate is either only weakly active or even inactive at K(ATP) channels in guinea pig airways or interacts with these channels in a different manner. The current results are consistent with there being differences between the K(ATP) channels in airways and blood vessels.

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Enzymatic and non-enzymatic sulfation mechanisms in the biological actions of minoxidil

Cited by 53 publications

References 25 publications

The Important Role of Bcrp (Abcg2) in the Biliary Excretion of Sulfate and Glucuronide Metabolites of Acetaminophen, 4-Methylumbelliferone, and Harmol in Mice

The Important Role of Bcrp (Abcg2) in the Biliary Excretion of Sulfate and Glucuronide Metabolites of Acetaminophen, 4-Methylumbelliferone, and Harmol in Mice

The Structure of Human SULT1A1 Crystallized with Estradiol

Atypical effect of minoxidil sulphate on guinea pig airways

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