Human cytosolic sulphotransferases: genetics, characteristics, toxicological aspects.

Cytosolic sulphotransferases transfer the sulpho moiety from the cofactor 5'-phosphoadenosine-3'-phosphosulphate (PAPS) to nucleophilic groups of xenobiotics and small endogenous compounds (such as hormones and neurotransmitters). This reaction often leads to products that can be excreted readily. However, other sulpho conjugates are strong electrophiles and may covalently bind with DNA and proteins. All known cytosolic sulphotransferases are members of an enzyme/gene superfamily termed SULT. In humans, 10 SULT genes are known. One of these genes encodes two different enzyme forms due to the use of alternative first exons. Different SULT forms substantially differ in their substrate specificity and tissue distribution. Genetic polymorphisms have been described for three human SULTs. Several allelic variants differ in functional properties, including the activation of promutagens. Only initial results are available from the analysis of SULT allele frequencies in different population groups, e.g. subjects suffering from specific diseases and corresponding controls.

Association between functional genetic polymorphisms of human sulfotransferases 1A1 and 1A2.

Three human phenol sulfotransferases, provisionally named SULT1A1, 1A2 and 1A3, show 91-96% homology of their amino acid sequences and are encoded by neighbouring gene loci. Functional genetic polymorphisms are known for two of these sulfotransferases. In SULT1A1, a G to A transition leads to an Arg213 to His exchange and eliminates a Bsp143II restriction site. SULT1A1*His shows lower enzyme activity and thermostability than SULT1A1*Arg. In SULT1A2, an A to C transversion causes an Asn235 to Thr exchange and introduces a BpiI restriction site. Enzyme SULT1A2*Thr is less active than SULT1A2*Asn. These substitutions were detected by restriction fragment length polymorphism analyses of genomic sequences amplified by polymerase chain reaction. Despite the high similarity between the different human SULT1A genes, it was possible to amplify specifically the polymorphic parts of either SULT1A1 or 1A2, but not the homologous sequences of the other SULT, by setting the forward primer into intron 6. DNA from 300 adult male Caucasian subjects was analysed. Allele frequencies were 0.63 and 0.37 for SULT1A1*Arg and *His, and 0.62 and 0.38 for SULT1A2*Asn and *Thr, respectively. The frequency of the haplotype SULT1A1*Arg/SULT1A2*Asn (0.61) was nearly as high as the allele frequencies of its components. The same was observed for the haplotype SULT1A1*His/SULT1A2*Thr, whose frequency was 0.35. In contrast, haplotypes 1A1*Arg/1A2*Thr and 1A1*His/1A2*Asn were very rare. Their frequencies (0.02 each) were less than 10% of the figures expected in an independent distribution. The results demonstrate a strong association of the alleles producing the more active enzyme variants (SULT1A1*Arg and SULT1A2*Asn) and of those encoding the less active variants (SULT1A1*His and SULT1A2*Thr).

Sulfotransferases: genetics and role in toxicology.

The mammalian xenobiotic-metabolizing sulfotransferases are cytosolic enzymes, which form a gene superfamily (SULT). Ten distinct human SULT forms are known. Two SULT forms represent splice variants, the other forms are encoded by separate genes. Common functional polymorphisms of the transcribed region are known for two of the forms. We have expressed 16 separate rat and human SULTs as well as some of their allelic variants, in Salmonella typhimurium TA1538 and/or V79 cells, which are target cells of commonly used mutagenicity assays. The expressed SULTs activated numerous compounds to mutagens in both assay systems. However, some promutagens were activated by only one or several of the human SULTs. Pronounced differences in promutagen activation were also detected between orthologous rat and human SULTs, and between allelic variants of human SULTs.