Glucuronidation relative rates

Tab. 13.1. Relative rates of glucuronidation in human liver and intestinal microsomes.

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. 

No discussion of this subject would be complete without emphasizing the point that the relative rates of hydrolysis of two substrates, which may be quite different from their relative affinities for an enzyme, may be at least as important as regards the physiological action of the enzyme. Dissociation constants measure affinity only (affinity = 1/dissociation constant). Thus, despite its 10-fold smaller affinity, phenyl /3-glucuronide is hydrolyzed nearly as rapidly as phenolphthalein /3-glucuronide by the purified enzyme from female-rat preputial gland at saturation with both substrates, in terms of moles of aglycon liberated.40 In the presence of a combined inhibitor (see Section IX, 3), there is a fall in the rate of hydrolysis, despite the increased affinity of the enzyme for the substrate. 

Formation of sulfates [328] is relatively reversible. This may be due to the fact that the metabolic clearance rate [318] of sulfates is relatively low [389] and their renal excretion inefficient [4]. The conversion of dehydroepiandrosterone sulfate in vivo to androsterone and etiocholanolone glucuronide was demonstrated by Lieberman and co-workers, who administered isotopically labeled dehydroepiandrosterone sulfate and isolated labeled androsterone and etiocholanolone from glucuronicase-hydrolyzed urine [303]. Since in another study by Lieberman [174], the transconjugation from dehydroepiandrosterone sulfate to dehydroepiandrosterone glucuronide without free dehydroepiandrosterone intermediate was declared to be improbable, in vivo equilibrium between dehydroepiandrosterone sulfate and dehydroepiandrosterone seems probable [303]. 

Isodrin is metabolized by biooxidation to endrin. Isodrin and its metabolite, endrin, have high fat water partition coefficients and, therefore, tend to accumulate in adipose tissue. At a constant rate of intake, however, the concentration of the insecticide in adipose tissue reaches an equilibrium and remains relatively constant. Following cessation of exposure, it is slowly eliminated from the body. In vitro studies have shown that mixed-function oxidase of mouse liver converts isodrin to endrin. Mice excrete 10% of the orally administered dose in urine. Four unidentified metabolites were present in urine, three probably are glucuronide or sulfate conjugates. Feces is... 

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