Sulfate conjugation in drug metabolism: role of inorganic sulfate.
ABSTRACT Conjugation with sulfate is a major pathway for the biotransformation of phenolic drugs in humans and many animal species. It is a process of limited capacity; the extent of sulfate conjugate formation and the metabolic clearance of drugs subject to conjugation with sulfate depend therefore on the dose, the dosage form, the route of administration, and the rate and duration of administration as well as on the pharmacokinetic parameters of competing processes. The effect of these variables is exemplified by the pharmacokinetics of salicylamide and acetaminophen in humans and rats. In our experience so far, the proximate cause of the nonlinear pharmacokinetics of sulfate conjugation of phenolic drugs is the limited availability and consequent depletion of inorganic sulfate. When this is prevented by direct or indirect (via sulfate donors such as N-acetylcysteine) repletion, the saturability of phenol sulfotransferase (EC 184.108.40.206) activity can become evident. The major mechanism of inorganic sulfate homeostasis is nonlinear renal clearance, which is due largely to saturable renal tubular reabsorption. Systemic depletion of inorganic sulfate secondary to utilization of this anion for the sulfation of drugs affects the availability of sulfate in the central nervous system and may, therefore, modify the disposition of certain neurotransmitters and other endogenous substances that are subject to sulfate conjugation.
- [show abstract] [hide abstract]
ABSTRACT: Chronic Fatigue/Immune Dysfunction Syndrome (CFIDS), a condition characterized by disabling fatigue, is difficult to manage clinically due to its diverse symptomatology. This study investigated use of a hepatic detoxification supplement and elimination diet in 14 CFIDS patients with compromised detoxification status, as assessed by caffeine clearance (phase I CYP1A2) and benzoate conversion (phase II glycine conjugation) assays. After intervention, most subjects reported a decrease in symptoms. Moreover, subjects who initially displayed the highest ratio of CYP1A2 to benzoate conversion showed statistically significant (pJournal of Advancement in Medicine 11/1998; 11(4):247-262.
- [show abstract] [hide abstract]
ABSTRACT: N-Acetyltransferases (NATs) and sulfotransferases (SULTs) are key phase II metabolizing enzymes that can be involved both in the detoxification and in the activation of many human promutagens and procarcinogens. We investigated the expression of NATs and SULTs in human prostate and tested their role in the activation the N-hydroxy (N-OH) metabolite of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), a dietary carcinogen, to form DNA adducts. Western blotting showed detectable levels of NAT1, SULT1A1 and SULT1A3 with marked inter-individual variation. NAT2 and other SULT enzymes were not detectable. NAT1 was localized by immunohistochemistry to the cytoplasm of epithelial cells. The presence of acetyl Co-enzyme A (acetyl CoA) and 3'-phosphoadenosine-5'-phosphosulfate (PAPS), NAT and SULT cofactors, respectively, significantly increased the level of DNA adducts, detected by P-postlabelling analysis, in calf thymus DNA incubated with N-OH-IQ and prostate cytosolic fractions. The enhancement in the level of DNA adducts in the presence of PAPS correlated with the level of SULT1A1 protein. A single prostate cytosol with the SULT1A1*2/*2 genotype produced less DNA adducts than cytosols with the *1/*2 and *1/*1 genotypes. No significant correlation was observed between NAT1 protein level and the formation of DNA adducts, even in the presence of acetyl CoA. In conclusion, we demonstrated that NAT1, SULT1A1 and SULT1A3 are present in human prostate and that both enzyme classes significantly contribute to the activation of N-hydroxylated heterocyclic amines to DNA-damaging species in this tissue. Variation in expression levels, in combination with dietary and/or environmental exposure to carcinogens, could be influential in determining individual susceptibility to prostate cancer.Pharmacogenetics and Genomics 07/2006; 16(6):391-9. · 3.61 Impact Factor
Article: Fetal hepatic drug elimination.[show abstract] [hide abstract]
ABSTRACT: The majority of studies of fetal hepatic elimination have concentrated on the expression and activity of the metabolizing enzymes, but the unique physiologic milieu of the fetal liver should also be considered. The basic structure of the liver is formed by the end of the first trimester. The fetal hepatic circulation differs substantially from that of the adult in that there is an extra input vessel, the umbilical vein, and there is shunting of 30-70% of hepatic blood flow via the ductus venosus. The left and right lobes of the fetal liver seem to function independently with respect to a variety of biochemical parameters, due at least in part to the lower oxygen supply to the right lobe. The zonation of drug-metabolizing enzymes along the hepatic acinus, which is prominent in the adult liver, is absent in the fetal liver. Unlike rodent species, the human fetal liver has a significant capacity for drug metabolism. Of the oxidative enzymes, CYP3A7 accounts for up to 50% of total fetal hepatic cytochrome P450 content. Expression of this enzyme decreases dramatically after birth. CYP1A1 and CYP2D6 have also been detected in human fetal liver, but whether CYP2E1 is expressed remains controversial. Several other cytochrome P450s have been identified and await characterization. Fetal hepatic drug conjugation may prolong fetal exposure to the metabolites produced, which, being more water soluble, do not readily cross the placenta back to the mother and, if excreted in fetal urine, can be recycled in the fetus via amniotic fluid and fetal swallowing. Limited activity of glucuronidation enzymes has been demonstrated in human fetal liver in contrast to the activity of sulfation enzymes, which is significant. Limited in vivo studies in fetal sheep have demonstrated significant fetal hepatic drug elimination, and this has been confirmed in studies of the isolated perfused fetal sheep liver. Our understanding of fetal hepatic elimination processes has advanced steadily over the years. Future developments, however, should consider more fully the influence of the unique physiological milieu of the fetal liver, in addition to the expression and activity of drug metabolizing enzymes.Pharmacology [?] Therapeutics 01/2000; 84(3):429-45. · 7.79 Impact Factor