Sulfate conjugation of phenols

The concept of microbial models of mammalian metabolism was elaborated by Smith and Rosazza for just such a purpose (27-32). In principle, this concept recognizes the fact that microorganisms catalyze the same types of metabolic reactions as do mammals (32), and they accomplish these by using essentially the same type of enzymes (29). Useful biotransformation reactions common to microbial and mammalian systems include all of the known Phase I and Phase II metabolic reactions implied, including aromatic hydroxylation (accompanied by the NIH shift), N- and O-dealkylations, and glucuronide and sulfate conjugations of phenol to name but a few (27-34). All of these reactions have value in studies with the alkaloids. 

In our previous studies on the sulfate conjugation of phenols by fish livers, all the liver slices of the test fish and shellfish exhibited sulfate conjugation activities with phenol(14), and among various liver cell fractions separated by ultracentrifugation, only the soluble fraction displayed the sulfate conjugation activity for phenol and various phenolic compounds(15). 

A number of enzymes known as sulfuric ester hydrolases (EC 3.1.6) are able to hydrolyze sulfuric acid esters. They comprise arylsulfatase (sulfatase, EC 3.1.6.1), steryl-sulfatase (steroid sulfatase, steryl-sulfate sulfohydrolase, arylsulfatase C, EC 3.1.6.2), choline-sulfatase (choline-sulfate sulfohydrolase, EC 3.1.6.6), and monomethyl-sulfatase (EC 3.1.6.16). Whereas mono-methyl-sulfatase is highly specific and does not act on higher homologues, arylsulfatase has a broad substrate specificity and is of particular significance in the hydrolysis of sulfate conjugates of phenols, be they endogenous compounds, drugs, or their metabolites [167-169],... 

Attention has already been made to the formation of glycoside and sulfate conjugates of phenolic metabolites during the biotransformation of polycyclic aromatic hydrocarbons by fungi (Section 6.2.2). Formation of sulfate esters is not, however, limited to fungal systems since this has been observed, for example, following 4 -hydroxylation of 5-hydroxyflavone in Streptomyces fulvissimus (Ibrahim and Abul-Hajj 1989), and the enzyme has been partly purified from a Eubacterium sp. (Koizumi et al. 1990). 

Ogata N, Matsushima N, Shibata T. 1995. Pharmacokinetics of wood creosote Glucuronic acid and sulfate conjugation of phenolic compounds. Pharmacology 51(3) 195-204. 

In terrestrial animals, the excreted products of PAHs are mainly conjugates formed from oxidative metabolites. These include glutathione conjugates of epoxides, and sulfate and glucuronide conjugates of phenols and diols. 

The present paper deals with a relation between toxicity and accumulation of chlorophenols in goldfish, Carassius auratus, PCP metabolites and their amounts excreted by the three major routes (branchial, renal and biliary) in the fish, and also with effects of pre-exposure to PCP on PCP-tolerance and on sulfate conjugation with phenol by the liver soluble fraction of the fish. 

Comparative Toxicokinetics. The metabolism and excretion of orally administered phenol in 18 animal species have been compared to metabolism and excretion in humans (Capel et al. 1972). The rat was the most similar to the human with respect to the fraction of administered dose excreted in urine in 24 hours (95%) and the number and relative abundance of the 4 principal metabolites excreted in urine (sulfate and glucuronide conjugates of phenol and 1,4-dihydroxybenzene). The rat excreted a larger fraction of the orally administered dose than the guinea pig or the rabbit (Capel et al. 1972) and appears to be the least susceptible of the three species to respiratory, cardiovascular, hepatic, renal, and neurological effects of inhaled phenol (Deichmann et al. 1944). More rapid metabolism and excretion of absorbed phenol may account for the lower sensitivity of the rat to systemic effects of phenol. More information on the relative rates of metabolism of phenol in various species is needed to identify the most appropriate animal model for studying potential health effects in humans. 

Table 5.12 Conjugation of Phenol with Glucuronic Acid and Sulfate...

The conjugation of phenol with glucuronic acid is zero in the cat but the facility is present in many other species. Conversely the conjugation of phenol with sulfate is zero in the pig but the facility is present in many other species. There are many... 

Studies on the metabolic fate of phenol in several species have indicated that four urinary products are excreted (Figure 9.5). Although extensive phenol metabolism takes place in most species, the relative proportions of each metabolite produced varies from species to species. In contrast to the cat, which selectively forms sulfate conjugates, the pig excretes phenol exclusively as the glucuronide. This defect in sulfate conjugation in the pig is restricted to only a few substrates, however, and may be due to the lack of a specific phenyl sulfotransferase because the formation of substantial amounts of the sulfate conjugate of 1-naphthol clearly indicates the occurrence of other forms of sulfotransferases. 

Some phenol is eliminated from the body as the unchanged molecular compound, although most is metabolized prior to excretion. As noted in Section 7.2.1, phase II reactions in the body result in the conjugation of phenol to produce sulfates and glucuronides. These water-soluble metabolic products are eliminated via the kidneys. Urinary phenyl glucuronide may be measured to monitor exposure to phenol.7... 

Hydroxylation of one or both aromatic rings Conjugation of phenolic metabolites with glucuronic acid or sulfate Scission of the N10 side-chain... 

Hydroxylation of one aromatic ring Conjugation of phenolic products with glucuronic acid or sulfate Hydrolytic scission of the hydantoin ring at the bond between carbons-3 and -4 to give 5,5-diphenylhydantoic acid... 

Kobayashi, K., S. Kimura and Y. Oshima. Sulfate conjugation of various phenols by liver-soluble fraction of goldfish. Bull. Jpn. Soc. Sci. Fish. 50 833-837, 1984. 

Miscellaneous methods. Sulfamic acid (NH2SO3H) has been used mainly In synthesis of sulfate conjugates of steroids (94.95). However the reaction, catalysed by pyridine and performed at 80-100 C for an hour, has also been used for phenolic subtrates (.77). Pyrldlnlum sulfate and acetic anhydride has been used for synthesis of estrone sulfate (9 ). 

Conjugation of phenolic compounds with formation of glucu-ronides, sulfates, or glucosides as noted above. 

Conjugation of phenols, aliphatic and steroid alcohols with sulfate occurs in mammals, birds, reptiles, amphibia, but not in fish. In addition, active sulfate in the presence of transferase will conjugate aromatic amines and form sulfamates [70] in mammals, birds, and spiders. The synthesis of sulfate derivatives occurs in the soluble fraction of liver homogenates through the formation of adenosine-5 -phosphosulfate (APS) and 3 -phosphoadenosine-5 -phosphosulfate (PAPS) [21]. The reactions may be written as follows ... 

At higher levels of phenols in the diet, glucuronic acid conjugation of phenols predominates over sulfate conjugation. This is attributed to the fact that the rate of glucuronic acid conjugation of phenols is proportional to the body levels of phenols. Sulfate conjugation, on the other hand, is independent of the phenol level and primarily depends upon the availability of sulfate in the body. Under normal circumstances, the byproducts of phenol metabolism are readily removed from the body by excretion via the kidneys. 

A study of the urinary metabolites of the hypnotic, flurazepam hydrochloride, Ro 5-6901 (III), in the dog reveals non-conjugated (IV) and (V), conjugated (IV), (V), (VI) and (VIII) and a phenolic derivative of (VII). Human urine contained only the glucosuronic acid or sulfate conjugate of (VI). The synthesis and a comparison of the pharmacology of flurazepam hydrochloride with that of other 1,4-benzodiazepines has been reported , as well as the clinical use of this compound as a hypnotic. ... 

Only the small amounts of T and T that are free in the circulation can be metabolized. The main route is deiodination of T to T and i-T, and from these to other inactive thyronines (21). Most of the Hberated iodide is reabsorbed in the kidney. Another route is the formation of glucuronide and sulfate conjugates at the 4 -OH in the Hver. These are then secreted in the bile and excreted in the feces as free phenols after hydrolysis in the lower gut. 

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