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DRUG METABOLISM REVIEWS

Vol. 36, Nos. 3 & 4, pp. 823-843, 2004

Sulfonation in Pharmacology and Toxicology*

Frederick C. Kauffman

Laboratory for Cellular and Biochemical Toxicology, Ernest Mario School

of Pharmacy, Rutgers, The State University of New Jersey,

Piscataway, New Jersey, USA

ABSTRACT

Sulfonation has a major function in modulating the biological activities of a wide

number of endogenous and foreign chemicals, including: drugs, toxic chemicals,

hormones, and neurotransmitters. The activation as well as inactivation of many

xenobiotics and endogenous compounds occurs via sulfonation. The process is

catalyzed by members of the cytosolic sulfotransferase (SULT) superfamily consisting

of at least ten functional genes in hum ans. The reaction in intact cells may be reversed

by arylsulafatase present in the endoplasmic reticulum. Under physiological

conditions, sulfonation is regulated, in part, by the supply of the co-substrate/donor

mo lecule 3'-phosphadensoine-5-phosphosu lfate (PAPS ), and transport mech anisms by

which sulfonated conjugates enter and leave cells. Variation in the response of

individuals to certain drugs and toxic chemicals may be related to genetic

polymorphisms documented to occur in each of the above pathways. Sulfonation

has a major function in regulating the endocrine status of an individual by modulating

the receptor activity of estrogens and androgens, steroid biosynthesis, and the

metabolism of catecholamines and iodothyronines Sulfonation is a key reaction in the

body's defense against injurious chemicals and may have a major function during

early development since SULTs are highly expressed in the human fetus. As with

Supported in part by NIEHS Center Grant No. ES05052.

*Correspondence: Frederick C. Kauffman, Laboratory for Cellular and Biochemical Toxicology,

Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ

08854 , USA ; E-mail: kauffma@ rci.rutgers.edu.


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82 4

KaufTman

many PhaseIand PhaseIIreactions, sulfonation may also serveasthe terminal stepin

activating certain dietary

and

environmental agents

to

very reactive toxic

intermediates implicated in carcinogenesis.

Key Words Sulfonation; Sulfation; Sulfotransferase; SULT; Sulfatase; PAPS.

INTRODUCTION

Sulfonation of low molecular weight compounds catalyzed by members of the

cytosolic sulfotransferase multigene family (SULT) is an important determinant of the

pharmacology and toxicology of a vast array of endogeneous and foreign chemicals

(Coughtrie, 2002; Strott, 2002). This pathway involves the transfer of a sulfonate group

(S0''~) from the universal donor 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to an

appropriate substrate. Sulfonated conjugates are often incorrectly referred to as

sulfates because the transfer of an SO ~ group to a hydroxyl acceptor creates an

SO *ester. Various components of the sulfonation pathway are summarized in Fig. 1.

The sulfonation system resides primarily in cytosol but involves interaction with

The ulfonation ystem

A T P . S O ,

^PS Kinase

Sulfotransferase:SULT

-SO4

- ROSO3

Cytosol

Endoplasm ic Reticulum Sulfatase:ARSc

Figure 1 Scheme depicting interactions between various factors that influencethe netformation

and transportof sulfonate esters from intact cells. Availabilityof the obligatory cofactory, PAPS,is

present at relatively low concentrations and may limit the synthesis of sulfonate conjugates

catalyzedbyvarious SULTs. PAPSisformed via a single bifunctional enzyme that contains both

ATP sulfurylase

and

APS activities. Inorganic sulfate

and two

molecules

of

A TP

are

required

for

each molecule of PAPS syntheisized. Sulfonate ester formation may also be reversed via the

hydrolytic enzyme arylsulfatas-c presentin theendolplasmic reticulum. Sulfonate conjugates leave


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Sulfonation in Pharm acology and Toxicology 8 5

arylsulfates-c (ARSc) in the endoplasmic reticulum and specific transport molecules

localized in the plasma membrane. Both organic acid transport molecules (OAT) (Buist

et al., 2003) and multidrug resistant proteins (mdrs) (Chu et al., 2004) have been

implicated in coupling sulfonate conjugate formation to transport from and into cells.

Sulfonate conjugates may also allosterically regulate mrp-mediated transport of other

conjugates such as glucuronides (Chu et al., 2004). PAPS is synthesized via ATP

sulfurylase and APS kinase which reside within a single bifunctional enzyme of

approximately 56 kDa (Lyle et al., 1994). Formation of sulfonated conjugates from

various substrates is catalyzed by cytosolic sulfotransferases (SULTs). Arylsulfatases

present in intact cells have the capacity to reverse the process of sulfonation in cells

and thus influence the process of net sulfonation (Coughtrie et al., 1998; Kauffman

et al., 1991; Tan and Pang, 2001). Under physiological conditions, each of these

components; availability of substrate and PAPS, as well as activities of both synthetic

SULTs and hydrolytic sulfatases, influence net availability of sulfonated conjugates.

The importance of sulfonation in modulating the function of many endogenous

compounds, including a large number of neurotransmitters and hormones as well as an

enormous number of xenobiotics in humans, is well established. Several excellent

reviews have appeared recently that consider progress made in understanding the

biological function of sulfonation and the regulation of expression of SULT isoforms in

specific tissues during critical periods of development (Coughtrie, 2002; Glatt et al.,

2001;

Strott, 2002). The object of this review is to highlight some important historical

aspects of the field and briefly review work on the sulfonation of xenobiotics and

endobiotics of particular interest to pharmacologists and toxicologists.

The process of sulfonation in biology was discovered in the late 19th century by

Eugen Baumann (1876), who isolated and characterized phenol sulfate from the urine

of a patient given phenol as an antiseptic. The enzymatic basis for the process was

discovered 80 years later when Lip ma nn's group discovered activ e sulfa te in their

pioneering studies on the metabolism of sulfanilamide (Robbins and Lippman, 1957).

This compound, which is the sulfuryl donor for most sulfonation reactions, is now

know to be 3-phosphoadenosyl- 5'-phosphosulfate (PAPS) (Klaassen and Bowles,

1997). Understanding the important role of sulfonation in the pharmacology and

toxicology of endogenous and foreign chemicals has advanced greatly since the

discovery of activ e sulfate, and in many ways has paralleled research with other

families of drug metabolizing enzymes including the cytochrome P450s and UDP

glucuronosyl transferases. Research underlying the great progress that has been made in

the past few years, due in large measure to the application of techniques in molecular

biology and modeling, is the subject of a number of recent reviews, (Coughtrie, 2002;

Weinshilboum et al., 1997). In light of Herbert Remmer's life time contributions to the

field of drug metabolism and his early work on both oxidative and conjugative

reactions (Bock et al., 1973; Remmer et al., 1975), he would be gratified by the

exciting work on sulfonation that has followed his pioneering studies.

Like many drug metabolizing enzymes, cytosolic SULTs compose a large

superfamily of genes. Full length cDNA for more than 50 mammalian and avian


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sequences. SULTl and SULT2 families are the largest and are responsible for

sulfonating the greatest number of endogen ous and foreign, com pound s. There are

currently 11 known isoforms of human SULT enzymes representing the SULTl,

SULT2, and SULT4 families (Coughtrie, 2002). These are products of 10 genes, with

alternate splicing occurring with the first exon of the SULT2B1 gene as reviewed in

(Weinshilboum et al., 1997). The expression of SULTs is carefully regulated in terms

of tissue type, development, and hormonal regulation. Some of the properties of known

human SULT isoforms with regard to major sites of expression and specificities for

endogenous and xenobiotic substrates are summarized in recent reviews by Coughtrie

and his colleagues (Coughtrie, 2002; Coughtrie et al., 1998). Despite considerable

research, endobiotic and xenobiotic ligands for a number of SULT isoforms remain to

be identified. An interesting example here is the failure to identify substrates for a

highly conserved protein (SULT4A1) identified from the expressed sequence database

that appears to be expressed only in mammalian brain (Falany et al., 2000; Liyou et al.,

2003; Sakakibara et al., 2002). This protein is prominent in a number of brain

structures including the cerebral cortex, cerebellum, pituitary, and brainstem of rats and

humans; however to date, no endogenous nor xenobiotic substrate has yet been

identified for SULT4A1.

PHARMACOGENTICS

Inter-individual variation in expression of SULT isoforms that have pharmacolog-

ical and toxicological significance in humans are well established [for reviews see

(Coughtrie, 2002; Weinshilboum and Aksoy, 1994)]. Considerable information exists

concerning the molecular basis underlying variation in SULT activities, and a number

of molecular epidemiological studies linking SULT polymorphisms to disease

susceptibility have appeared (Bamber et al., 2001; Seth et al., 2000; Zheng et al.,

2001).

Pioneering studies carried out by Weinshilboum and his colleagues showed that

platelet phenol sulfotransferase activity and thermal stability were related to SULTIAl

genotype (H aenen et al., 19 91; Weinshilboum and Aksoy, 1994). The availability of a

simple colorimetric assay, and the presence of thermal stable and thermal labile forms

of phenol sulfotransferase in platelets, an easily accessible tissue, opened the possibility

of initiating studies into the heritability of biochemically distinct forms of SULT. Early

studies employing biochemical measurements showed that genetically determined

variation in the thermal stability of phenol sulfotransferase in platelets correlated with

individual differences in sulfonation of acetaminophen after oral administration (Reiter

and Weinshilboum, 1982). Using 4-nitrophenol as a substrate, Raftogianis et al. (1997)

observed m ore than a 50-fold variation in the activity of phenol sulfotransferase from

905 subjects. This enzyme, now known as SU L TI A l, is a broad spectru m

sulfotransferase involved in the metabolism and detoxification of many drugs and other

foreign chemicals as well as the bioactivation of many dietary and environmental

procarcinogens (Coughtrie and Johnston, 20 01 ; Glatt et al., 2000).


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in the coding region of this enzyme in humans Cough trie, 2002; Weinshilboum and

Otterness, 1994). The two most common S UL TIA l alleles, termed SULT1A 1*1 and

SULT1A1*2, determined by gene sequencing studies involve a single amino acid

change at position 213. The allelic variant that possesses an arginine at position 213

SUL T1A 1*1) is more thermostabile than the variant containing histadine at this

position SU LT IA 1*2) when using p-nitrophenol as substrate. Pioneering work by

Weinshilboum and his colleagues showed that platelet enzyme activity and thermal

stability were related to SULTIAl genotype. Individuals with the SULTIAl*2

genotype had significantly lower platelet activity than 1A1*1/1A1*2 heterozygotes or

1A1*1 homozyg otes Raftogianis et al., 1997). The reduced activity noted in

SULTIAl*2 genotypes is likely due to alterations in amounts of expressed enzyme

since kinetic properties of recombinant SULTIAl isoforms failed to demonstrate

reduced activity of the 1A1*2 allozyme Li et al., 20 01 ; Tabrett and Coughtrie, 2003).

A reduced biological half-life due to enhanced proteosomal degradation has been

suggested as a possible mechanism accounting for low amounts of the SULTIAl*2

allozyme Coug htrie, 2002).

The occurrence of a common functional polymorphism in SU LT IA l has

stimulated a number of molecular epidemiological studies attempting to link individual

variation in SU LT IA l activity with certain pathologies notably breast Nowell et al.,

2002a; Saintot et al.,

2003;

Seth et al., 2000; Zheng et al., 2001), colon Bam ber et al.,

2001; Liang et al., 2003), prostate Nowell et al., 2004), and lung Liang et al., 2003)

cancers. Although these studies have produced confiicting results, they are valuable in

identifying associations that may occur between certain physiological factors, life

styles, and SULTIAl genotypes. For example, a significant increase in the frequency

of the wild type allele, SULTlAl*l, was noted in older individuals in a small

population-based study suggesting that the high sulfonation phenotype provided

protection against long term tissue damage arising from exposures to endogenous

chem icals or xenobiotcs with aging Cough trie et al., 1999). In contrast, several case

control studies concerning the onset of various cancers mentioned above suggest an

association between the high activity SULT1A]*1 allele and heightened risk of these

diseases in human populations. There is at least one study indicating that homozygosity

for the SU LT ]A 1*2 allele slightly reduced the risk for colorectal cancer Nowell

et al., 2002b).

A potential link between high activity and SULTIAl and increased risk from

certain dietary constituents has been suggested. A large number of environmental

mutagens and carcinogens, such as heterocyclic amines contained in well done meat,

are activated by sulfotransferases Glatt, 2000) . The risk of early-onset breast cancer as

well as the occurrence of other tumors may be increased in individuals having higher

amounts the SU LT IA l allele compared to controls Seth et al., 2000). Several studies

suggesting that variations in SU L TI A l alleles contribute to the risk of breast Zheng

et al., 2001) and prostate Now ell et al., 2004 ) cancer implied that risk to these cancers

was increased by the consumption of well done meats. Findings such as these, as well

as those of other studies, emphasize the importance of considering associations between


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8 8 Kauffman

evidence is emerging that variation in these genes also contribute to pathophysiology in

humans. Sequencing of DNA samples for 60 African Americans and 60 Caucasian

Am erican subjects identified o ne non-synonymous SN P Lys234A rg) only in A frican

Am erican subjects Thom ae et al., 2003). Heterologous expression of this variant in

COS cells indicated decreased sulfonation of dopamine compared to wild type enzyme

expressed in the same system. A significant decrease in immunoreactive protein

compared to that of the wild type sequence was noted. Kinetic properties of the two

recombinant proteins did not differ. The authors provide data that this single amino

acid change leads to accelerated degradation through a proteosome-mediated process

Thomae et al., 2003).

Estrogen sulfotransferase SU L TI EI ) has the lowest Km values for estrogens of

the 11 known human SULT enzymes. A number of studies suggest that inter-individual

variation in the activity of this isoform is associated with the pathophysiology of

hormone-dependent diseases such as breast cancer. Using the same cohort of African

American and Caucasian Americans described above, Weinshilboum and his colleagues

identified three non-synonymous SNPs that were associated with altered levels of

expression and kinetic properties of sequences expressed heterologously in COS-1 cells

Adjei et al., 2003) . Such findings lend further crede nce to the idea that g enetically

determined variation in SULTIEI catalyzed sulfonation of estrogens contributes to the

pathophysiology of estrogen-dependent diseases as well as the biotransformation of

estrogens administered pharmacologically. Application of DNA sequencing and

analysis of the SULT2A1 gene and expression constructs derived from the same

cohort above identified three functional SNPs in DNA from African American subjects

Thomae et al., 2001). The most common of these non-synonymous SNPs occurred in

the dimerization motive Petrotchenko et al., 2001) that influenced the dimerization of

SULT2A1 in vitro.

PAPS is synthesized from ATP and inorganic sulfate by two isoforms of PAPS

synthetase PA PSSl and PAPSS 2) Besset et al., 2000; Xu et al., 2000 ). A rare

polymorphism GLU 532) in the PA PSSl identified in DNA from an African Am erican

subject was associated with a five-fold higher Km for inorganic sulfate compared to the

wild-typ e allozym e Xu et al., 2003). It is not known if this genetic variation in

PAPSSl is associated with decreased PAPS synthesis and altered sulfonate conjugation

in vivo.

SULFONATION OF ENDOGENOUS AND

FOREIGN CHEMICALS

Sulfotransferses from each of the major subfamilies of this group of enzymes are

involved in metabolism of broad classes of foreign and endogenous compounds. There

are several recent excellent reviews summarizing these reactions. An earlier review by

Miller and Surh 1994) summ arized the key function that sulfonation has in the

activation of a wide array of chemical carcinogens. There are also several recent


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Sulfonation in Pharmacology and Toxicology

8 9

Table 1

Selected substrates for mam malian sulfotransferases.

Substrate SULT isoform Reference

Etidogettous chemicals

Catecholamines

Iodothyronines

Ascorbic acid

Vitamin D

Cholesterol

Estrogens

Dhydroepiandrosterone

Androgens

Neurosteroids

Bile acids

Xenobiotics

Drugs

Acetaminophen

Apomorphine

Butesonide

Ethinylestradiol

Minoxidil

Tamoxifen

Dietary constituents

Curcumin

Flavonoids

S U L T

lAl,

S U L T

1A3

SULTIAl

SULTIAl

SULT2A1

SULT2Blb

SULTIEI, lAl,1A 2

SULT2A1

SULTIAl

SULT2A1

SULT2A1

SULTIAl

SULTIAl,1A2,

1A3,lEl

SULT2A1

SULTIAl

SULTIAl,lCl

SULTIAl

SULTIAl,

IA3

SUL TIA l, 1A3,lCl

Buuetal.,1981;

Eisenhofer et al., 1999;

Taskinen et al.,

2003;

Thomae et al., 2003)

Kester et al.,

2003;

Li and Anderson, 1999;

Li et al., 2000; Rubin et al., 1999;

Visser, 1994; Visser et al., 1998)

Tolbert, 1985)

Axelson, 1985;

Echchgadda et al., 2004)

Strott and Higashi,

2003;

Yanai et al., 2004)

Adjei and Weinshilboum, 2002;

Mancini et al., 1992;

Purinton and Wood, 2000;

Qian et al., 2001)

Shimada et al., 2001;

Sugahara et al., 2003)

Chang et al., 2004)

Cascio et al., 2000;

Krueger and Papadopoulos, 1992;

Markowski et al., 2001)

Frye and Lacey, 1999;

Kitada et al.,

2003;

Palmer and Bolt, 1971;

Shen et al., 2000;

Song et al., 2001)

Reiter and Weinshilboum, 1982)

LeWitt, 2004;

Thomas and Coughtrie, 2003)

Meloche et al., 2002)

Chu et al., 2004)

Dooley, 1999;

Meisheri et al., 1993)

Chen et al, 2002;

Glatt et al., 1998)

Ireson et al., 2002)

Mesia-Vela and Kauffman,

2003;

Pai et al., 2001;


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830 Kauffman

able 1 Continued.

Substrate

oxic chemicals

Pro carcinogens

Aliphatic and

benzylic alcohols

Alkenylbenzenes

Aromatic amines

and amides

Heterocyclic

aromatic amines

Polynuclear aromatic

hydrocarbons

Others

Perflorocarboxylic acids

Manganese

SULT isoform

SULT2A1

SULTIAl

SULTIAl, SULTIC

SULTIAl, 1A2, IA3

SULTI Al

SULTI Al

SULTI Al

Reference

(Miller and Surh, 1994)

(Duffel etal., 2001;

Glatt et al., 2000)

(Boberg et al., 1983)

(Glatt and Meinl, 2004;

King and Phillips, 1968;

Sakakibara et al., 1998)

(Buonarati et al., 1990;

Sugimura, 2002)

(Tiemersma et al., 2004;

Watabe etal., 1982)

(Witzmann et al., 1996)

(Ranasinghe et al., 2000)

b io t r a n s f o r ma t io n o f e n d o g e n e o u s c o mp o u n d s ( Co u g h t r i e , 2 0 0 2 ; S t r o t t , 2 0 0 2 ) .

Members of the SULT2A family a re pr imar i ly assoc ia ted with the metabol ism of

hydroxys te ro ids (Th om ae e t a l . , 20 01 ; W einsh i lbo um and Otte rness , 1994) . Se lec ted

examples of the function of sulfonation in the biotransformation of endogenous

com poun ds and xenobio t ics a re sum mar ized in Table 1 and brie fly d iscussed be low .

Endogenous Chemicals

Sulfonation has been recognized as a pathway for catecholamine inactivation in

man and an imals for at least 3 deca des (Buu et al., 1981 ; Roth and R ivett, 1982), and it

has been estimated that as much as 10% of the metabolism of dopamine and

norepinephrine in brain may be inactivated by this pathway (Rivett et al., 1982;

Whittemore and Roth, 1985). Most catechois studied are substrates for SULT isoforms

l A l , 1A2, 1A3, and l B l (Taskinen et al., 2003). A functional genetic polymorphysim

recently reported for human SULT 1A3 has been associated with accelerated

degradation via a proteosomal-mediated process (Thomae et al., 2003). Authors of

this report raised the possibility that such changes may be related to inherited

alterations in catecholamine sulfonation in humans. Dopamine sulfate exists at much

higher concentrations in human plasma than dopamine and appears to arise mainly

from dietary biogneic amines and sulfonation of dopamine produced in the myenteric

plexus of the gastroinitestinal tract via SULTl

A

which is expressed in large amounts

in the gastrointestinal tract (Eisenhofer et al., 1999). It has been suggested that more

than 75% of dopamine sulfate present in the body is produced via this pathway which

serves as a gu t-b loo d barrier for dietary biogenic amines and dopam ine produced in


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Sulfonation in Pharm acology and Toxicology 83

have been linked to important developmental processes (Coughtrie, 2002). For ex-

ample, production of DHEA sulfate via SULT2A1 by the fetal adrenal is established as

a critical step in providing substrate for estrogen biosynthesis by the placenta during

pregnancy (Barker et al., 1994). Thyroid hormone bioavailability in the human fetus is

regulated, in part, by enzymatic deiodination and reversible sulfonation of

iodothyronines (Hume et al., 2001). Sulfonation of 3,3 -diiodothyronine was found to

correlate with SU LT IA l in a wide range of fetal tissues suggesting that this isoform is

primarily responsible for sulfonation of this hormone in fetal tissues (Richard et al.,

2001). SULTIAl may serve an important defense mechanism in the fetus since other

metabolic pathways are very low or absent in fetal tissues, and the human fetus

produces very high amounts of iodothyronine sulfates (Coughtrie, 2002).

Cholesterol sulfate and DHEA sulfate are the two most abundant sterol sulfonates

in the human circulation (Strott and Higashi, 2003). Their concentrations overlap and

range between 2 to 6 [xM in blood; how ever, w hile blood levels of cholesterol sulfate

remain relatively constant throughout life, levels of DHEA sulfate peak at puberty and

decline with age (Orentreich et al., 1984). Much is known about the physiological

function of the former in contrast to DHEA sulfate which, in large, remains a mystery.

In contrast, considerable information exists concerning the role of cholesterol sulfate as

a regulatory molecule in a variety of processes, e.g., keratinocyte differentiation,

epidermal and platelet cell adhesion, sperm capacitation, blood clotting, and fibrinolysis

(Strott and Higashi, 2003). Both compounds are sulfonated by members of the SULT2

family, which are primarily involved in the conjugation of neutral steroids and sterols.

DHEA is considered as the primary substrate for SULTIAl, which is also referred to

as DHE A sulfotransferase or hydroxysulfotransferase (Nagata and Yamaz oe, 2000 ).

SULT2B has been further divided into two isoforms derived from the same gene

(SULTIBI) differing in structure and substrate specificity; SULT2Bla and SULT2Blb

(Her et al., 1998). SULT2Blb acitively sulfonates cholesterol while SULT2Bla

sulfonates pregnenolone but not cholesterol (Fuda et al., 2002; Strott and Higashi,

2003). The recent finding that SULT2Blb is expressed in human platelets (Yanai et al.,

2004) enhances the opportunity to explore potential polymorphisms in this gene and

relationships to altered physiological processes regulated by cholesterol sulfate.

The term

neurosteroi s

designates steroids that are newly synthesized from

cholesterol or other precursors in the nervous system, and are still present in substantial

amounts after removal of peripheral steroidogenic organs (Mensah-Nyagan et al.,

1999). Initial steps in the synthesis of neurosteroids from cholesterol involves of

number of cytochrome P450s localized in brain (Hojo et al., 2004; Shibuya et al.,

2003). Sulfonation in brain is particularly important because a variety of neuro-

transmitter systems including GABA (Baulieu, 1998; Sullivan and Moenter, 2003),

cholinergic (Rhodes et al., 1997), glutaminergic (Flood et al., 1999) and a-opioid

(Monnet et al., 1995) receptors are modulated by both free and sulfonated neuro-

steroids, often in opposing ways. For example, pregnenolone is a barbiturate-like ago-

nist, whereas its sulfonated conjugates acts as a picrotoxin-like antagonist (Krueger and

Papadopoulos, 1992; Melchior and Allen, 1992). Dehydroepiandrosterone sulfate en-

hances acetylcholine release from the hippocampus while the unconjugated form does


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Sulfonation in Pharmacology andToxicology 833

these inhibitors are polyphenols such as quereetin (Mesia-Vela and Kauffman, 2003;

Walle et al., 1995), ingredients in red wine (Jones et al., 1995), and tea and coffee

(Coughtrie et al., 1998). Tests with recombinant SULTl isofoms indicated that SULTs

lA l, 1A2, and 1A3 are inhibited to varying degrees by a wide range of dietary

polyphenols; however, the most potent inhibitors found in this class of chemicals were

epicatechin gallate, epigallocatechin, and gallocatechin gallate (Coughtrie and Johnston,

2001). Further kinetic experiments in this same study indicated that inhibitory potency

toward each of the three isoforms varied considerably with SULTIAl being the most

sensitive. Ki values for epicatechin gallate and epigallocatechin gallate were 64 nm and

42 nm, respectively. Further studies to determine the possibility that compounds such

as the gallates in tea and coffee modulate variants of SULTIAl in human subjects in

vivo and the consequences of such effects would be valuable.

Toxic hemicals

It is well established that sulfotransferases bioactivate a host of chemicals, many of

which are dietary constituents, to reactive intermediates that are implicated in

carcinogenesis. Much of our understanding of the involvement of reactive sulfuric acid

esters in chemical carcinogenesis stems from the pioneering work of James and

Elizabeth Miller (Miller, 1970). Examples of chemicals that are converted to DNA- and

protein adducting species by sulfonation include benzylic alcohols of polycyclic

aromatic hydrocarbons (PAHs), estragole, safrole, as well as various hydoroxyaryl-

amines, arylhydroxamic acids formed from heterocyclic amines found in cooked meat

and fish (Miller and Surh, 1994). A principle pathway for chemical carcinogenesis is

the formation of toxic and very reactive sulfuric acid esters that undergo heterocyclic

cleavage to generate sulfate ions and potent electrophiles that combine.avidly with

nucleophilic groups in cellular DNA and proteins. Much recent work in toxicology has

been devoted to defining the activation of various pro-carcinogens by specific SULT

isoforms (Glatt and Meinl, 2004; Glatt et al., 1995; Sakakibara et al., 1998). A recent

study of nitrofen, that had been used as a herbicide in Germany until its carcinogenic

and teratogenic activities were detected in rodents, illustrates the principle of using

genetically manipulated strains of

almonella typhimuium

to evaluate the role of

specific SULT isoforms in mutagenagenesis (Glatt and Meinl, 2004).

Further appreciation for the importance of sulfonation in toxicology comes from

the finding that a number of hydroxylated metabolites of polychlorinated biphenyls are

extremely potent inhibitors of SU LT IE I with Ki s in the picomolar range (K ester et al.,

2000 ). Since SU LT IEI is the primary enzyme responsible for inactivation of estrogens

in humans, the authors suggest that the endocrine disrupting effects of these ubiquitous

environmental pollutants occur via the high capacity of their hydroxylated metabolites

to inhibit estrogen sulfonation via SULTIAl.

FUTURE DIRE TIONS


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8 4 Kauffman

function during fetal and early postnatal life including biotransformation of many

endogenous and foreign chemicals. It will be important to gain further understanding of

mechanisms regulating the expression of various elements of the sulfonation system and

the physiological consequences of alterations in this system during early life.

Evidence collected over the last decade suggest that sulfonation is critical to

regulating the actions of steroids within the central nervous system. Important questions

concerning mechanisms regulating the expression of various elements of the sulfonation

system in brain and other tissues remain to be answered. Some elements involved in

regulating expression of cytochrome P450 enzymes may also function in transcrip-

tionally inducing cytosolic sulfotranferases. For example, the vitamin D receptor

mediating nuclear signaling, known to induce cytochrome P450 expression also appears

to be involved along with the farnesoid X nuclear receptor in stimulating endogenous

SULT2A 1 expression Echchgadda et al., 2004; Song et al., 2001). Progress is being

made in understanding the regulation of this isofrom e.g., Runge-M orris et al., 1999);

however there is little known concerning mechanisms regulating the expression of other

SULT isoforms.

Finally, progress in understanding interactions between the different components of

the sulfonation system in various organs and tissues is emerging. Recent work

employing mRNA expression and immunohistochemistry has localized steroid sulfatase

and various organic acid transport proteins in biopsy samples of human temporal lobe

Steckelbroeck et al., 2004). It is tempting to speculate that these components function

together with de novo biosynthesis of DHEA-sulfonate and other 3-3-hydroxy steroids

to regulate levels of these steroids at critical sites in the brain.

R F R N S

Adjei, A. A., Weinshilboum, R. M. 2002). Catecholestrogen sulfation; p ossible role in

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