Sulfotransferase inhibition: potential impact of diet and environmental chemicals on steroid metabolism and drug detoxification.
The cytosolic sulfotransferase enzymes (SULT isoforms) utilise PAPS (3'-phosphoadenosine-5'-phosphosulfate) as co-factor to transfer sulfonate groups onto a wide range of substrates. SULT1A3 has catecholamines such as dopamine as substrates while SULT 1E1 sulfonates oestrogens. SULT 1A1 sulfonates phenols and also oestrogens at a higher K(m) than SULT 1E1. SULT 2A1 mainly sulfonates DHEA and some steroids, with hydroxy derivatives of polycyclic aromatic hydrocarbons. Studies on these isoforms with a range of environmental chemicals and dietary components have shown that SULT 1A1 is significantly inhibited by flavonoids; all flavones and flavonols with a 3',4'-dihydroxy motif had an IC(50) of < 100 nm against 3 microM 4-nitrophenol as the standard substrate. SULTs 1A3 and 2A1 were less strongly inhibited by flavonoids or isoflavonoids although tricin (3',5'-dimethoxy-4',5,7-trihydroxyflavone is a competitive inhibitor of SULT 1E1 with an inhibition constant of approximately 1 nM. Fruit and vegetable cytosols also inhibit SULT isoforms, as do long-chain alkylphenols and chlorinated phenols. Phthalates (used as plasticisers) inhibited SULTs 1E1 and 2A1. As these environmental contaminants and dietary components all act at the same site, their effects would be expected to be additive and could potentially therefore reduce sulfonation of drugs and lead to altered pharmacological responses.
Harris
R M
RM
School of Biosciences, University of Birmingham, Birmingham, UK. R.M.Harris@bham.ac.uk
Waring
R H
RH
D000818:Animals; D004032:Diet; D052244:Endocrine Disruptors / Q000737:chemistry / Q000633:toxicity*; D004785:Environmental Pollutants / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D008658:Inactivation, Metabolic / Q000502:physiology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D013256:Steroids / Q000378:metabolism*; D015238:Sulfotransferases / Q000037:antagonists & inhibitors*
D052244:Endocrine Disruptors; D004785:Environmental Pollutants; D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D013256:Steroids; D015238:Sulfotransferases