Human and rat liver phenol sulfotransferase: Structure-activity relationships for phenolic substrates

N. R C Campbell, J. A. Van Loon, R. S. Sundaram, M. M. Ames, C. Hansch, Richard M Weinshilboum

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Abstract

Phenol sulfotransferase (PST) catalyzes the sulfate conjugation of many phenolic drugs. Human liver contains thermostable (TS) and thermolabile forms of PST. Ion exchange chromatography shows that two isozymes of TS PST (peaks I and II) are present in human liver preparations. Rat liver contains four forms of PST that can be separated by ion exchange chromatography. Quantitative structure-activity relationship (QSAR) analysis was used to study phenolic substrates for both human and rat liver PST. Thirty-six substituted phenols were tested as substrates for partially purified human liver TS PST peak I. QSAR analysis resulted in derivation of the following equation: log 1/K(m) = 0.92 (±0.18)log P- 1.48 (±0.38)MR'4 - 0.64 (±0.41)MR3 + 1.04 (±0.63)MR2 + 0.67(±0.44) σ- + 4.03 (±0.42). In this equation K(m) is the Michaelis constant, P is the octanol-water partition coefficient, MR is the molar refractivity of substituents at the 2-,3-, and 4-positions, and σ- is the Hammett constant. Values of log 1/K(m) calculated with this equation were highly correlated with log 1/K(m) values (r=0.950) that were observed experimentally. Nine phenols were also tested as substrates for partially purified human liver TS PST peak II. Log 1/K(m) values for these compounds were significantly correlated for the two isozymes of TS PST (r=0.992, p < 0.001). QSAR analysis was also used to derive equations that described the behavior of phenolic substrates for rat liver PST forms I and II. These equations differed substantially from the equation derived for compounds tested with human liver TS PST peak I. Therefore, the characteristics of the active sites of human liver TS PST peak I and rat liver PST forms I and II appear to differ. Application of these equations may make it possible to predict K(m) values of phenolic substrates for human liver TS PST and for rat liver PST forms I and II.

Original languageEnglish (US)
Pages (from-to)813-819
Number of pages7
JournalMolecular Pharmacology
Volume32
Issue number6
StatePublished - 1987

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Arylsulfotransferase
Structure-Activity Relationship
Liver
Quantitative Structure-Activity Relationship
Phenols
Ion Exchange Chromatography
Isoenzymes
Octanols

ASJC Scopus subject areas

  • Pharmacology

Cite this

Campbell, N. R. C., Van Loon, J. A., Sundaram, R. S., Ames, M. M., Hansch, C., & Weinshilboum, R. M. (1987). Human and rat liver phenol sulfotransferase: Structure-activity relationships for phenolic substrates. Molecular Pharmacology, 32(6), 813-819.

Human and rat liver phenol sulfotransferase : Structure-activity relationships for phenolic substrates. / Campbell, N. R C; Van Loon, J. A.; Sundaram, R. S.; Ames, M. M.; Hansch, C.; Weinshilboum, Richard M.

In: Molecular Pharmacology, Vol. 32, No. 6, 1987, p. 813-819.

Research output: Contribution to journalArticle

Campbell, NRC, Van Loon, JA, Sundaram, RS, Ames, MM, Hansch, C & Weinshilboum, RM 1987, 'Human and rat liver phenol sulfotransferase: Structure-activity relationships for phenolic substrates', Molecular Pharmacology, vol. 32, no. 6, pp. 813-819.
Campbell, N. R C ; Van Loon, J. A. ; Sundaram, R. S. ; Ames, M. M. ; Hansch, C. ; Weinshilboum, Richard M. / Human and rat liver phenol sulfotransferase : Structure-activity relationships for phenolic substrates. In: Molecular Pharmacology. 1987 ; Vol. 32, No. 6. pp. 813-819.
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T2 - Structure-activity relationships for phenolic substrates

AU - Campbell, N. R C

AU - Van Loon, J. A.

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AU - Ames, M. M.

AU - Hansch, C.

AU - Weinshilboum, Richard M

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N2 - Phenol sulfotransferase (PST) catalyzes the sulfate conjugation of many phenolic drugs. Human liver contains thermostable (TS) and thermolabile forms of PST. Ion exchange chromatography shows that two isozymes of TS PST (peaks I and II) are present in human liver preparations. Rat liver contains four forms of PST that can be separated by ion exchange chromatography. Quantitative structure-activity relationship (QSAR) analysis was used to study phenolic substrates for both human and rat liver PST. Thirty-six substituted phenols were tested as substrates for partially purified human liver TS PST peak I. QSAR analysis resulted in derivation of the following equation: log 1/K(m) = 0.92 (±0.18)log P- 1.48 (±0.38)MR'4 - 0.64 (±0.41)MR3 + 1.04 (±0.63)MR2 + 0.67(±0.44) σ- + 4.03 (±0.42). In this equation K(m) is the Michaelis constant, P is the octanol-water partition coefficient, MR is the molar refractivity of substituents at the 2-,3-, and 4-positions, and σ- is the Hammett constant. Values of log 1/K(m) calculated with this equation were highly correlated with log 1/K(m) values (r=0.950) that were observed experimentally. Nine phenols were also tested as substrates for partially purified human liver TS PST peak II. Log 1/K(m) values for these compounds were significantly correlated for the two isozymes of TS PST (r=0.992, p < 0.001). QSAR analysis was also used to derive equations that described the behavior of phenolic substrates for rat liver PST forms I and II. These equations differed substantially from the equation derived for compounds tested with human liver TS PST peak I. Therefore, the characteristics of the active sites of human liver TS PST peak I and rat liver PST forms I and II appear to differ. Application of these equations may make it possible to predict K(m) values of phenolic substrates for human liver TS PST and for rat liver PST forms I and II.

AB - Phenol sulfotransferase (PST) catalyzes the sulfate conjugation of many phenolic drugs. Human liver contains thermostable (TS) and thermolabile forms of PST. Ion exchange chromatography shows that two isozymes of TS PST (peaks I and II) are present in human liver preparations. Rat liver contains four forms of PST that can be separated by ion exchange chromatography. Quantitative structure-activity relationship (QSAR) analysis was used to study phenolic substrates for both human and rat liver PST. Thirty-six substituted phenols were tested as substrates for partially purified human liver TS PST peak I. QSAR analysis resulted in derivation of the following equation: log 1/K(m) = 0.92 (±0.18)log P- 1.48 (±0.38)MR'4 - 0.64 (±0.41)MR3 + 1.04 (±0.63)MR2 + 0.67(±0.44) σ- + 4.03 (±0.42). In this equation K(m) is the Michaelis constant, P is the octanol-water partition coefficient, MR is the molar refractivity of substituents at the 2-,3-, and 4-positions, and σ- is the Hammett constant. Values of log 1/K(m) calculated with this equation were highly correlated with log 1/K(m) values (r=0.950) that were observed experimentally. Nine phenols were also tested as substrates for partially purified human liver TS PST peak II. Log 1/K(m) values for these compounds were significantly correlated for the two isozymes of TS PST (r=0.992, p < 0.001). QSAR analysis was also used to derive equations that described the behavior of phenolic substrates for rat liver PST forms I and II. These equations differed substantially from the equation derived for compounds tested with human liver TS PST peak I. Therefore, the characteristics of the active sites of human liver TS PST peak I and rat liver PST forms I and II appear to differ. Application of these equations may make it possible to predict K(m) values of phenolic substrates for human liver TS PST and for rat liver PST forms I and II.

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