Glucuronic acid transfer

The predicted metabolites are also the starting point for the phase II metabolic prediction, to find where glucuronidation could occur. All the probable metabolites obtained from CYP metabolism reactions are submitted to a possible phase II reaction catalyzed by UGTs, using the UGT structure(s) as a template. The accessibility component is computed in the UGTcavity to prioritize glucuronic acid transfer. The final metabolite structures are then reported in graphical output or saved to a file. 

Glucuronidation involves the transfer of D-glucuronic acid from UDP-a-glu-curonic acid to an acceptor compound. The family of enzymes which catalyze this reaction are the UDP-glucuronyl transferases [16]. The reaction proceeds by nucleophilic Sn2 substitution of the C-1 carbon of glucuronic acid, the product undergoing inversion of configuration. The mechanism is illustrated schematically in Figure 7.21. 

With washed microsomal preparations from the liver of guinea pig, rat, rabbit, mouse, and cat, conjugation of bilirubin also occurred at appreciable rates in the absence of added bivalent cation (P3). With digitonin-activated preparations from rat liver, glycosyl transfer rates were, respectively, 16-33%, 0-38%, and 58-78% of the values found at nearsaturation of Mg + when UDP-glucuronic acid, UDP-xylose, or UDP-glucose were assayed (F3, HIO). The great variability of the rates could point to an artifact. 

In the procedure of Wong (W12) bilirubin is incubated enzymatically with [U- C]UDP-glucuronic acid of known specific activity. The derived azo pigments are transferred quantitatively to a thin-layer plate and are separated. The spot of conjugated azo pigment is eluted and counted. With other radioactive UDP-sugars, extension of the procedure to the corresponding transfer processes is obvious. 

In these experiments, several doubly and triply labelled compounds were reported.108 So-called UDP-D-[U-I4C, 3,4- H]glucuronic acid was formed by mixing UDP-D-[U-14C]glucuronic acid, UDP-d-[3-3H]glucuronic acid, and UDP-D-[4-3H]glucuronic acid it was not, of course, a triply labelled compound, but a mixture of 3 singly labelled ones.108 This factor prevented any conclusions about intramolecular transfer with doubly or triply labelled compounds to be reached. 

Kauss (39) has shown that the esterification of the carboxyl groups in the D-galacturonic acid chain takes place by a transfer of the methyl groups from S-adenosyl-L-methionine, analogous to the case in which the 4-methyl ether groups are transferred to D-glucuronic acid of hemi-cellulose (40). 

As previously mentioned, Kauss (40) has shown that the methyl donor for the formation of 4-methyl-D-glucuronic acid of hemicellulose B proved to be S-adenosyl-L-methionine, the same as in pectin. A particulate preparation from immature com cobs containing hemicellulose B was found capable of transferring the 14C-labeled methyl group from S-adeno-syl-L-methionine to a macromolecular acceptor present in the particles. The radioactive product was shown to be hemicellulose B labeled in the 4-methyl-D-glucuronic acid residues. It was isolated chiefly as 4-methyl-glucuronosyl-( 1 - 2)-D-xylose. 

Many Anabolic/Androgenic Steroids (AAS) are available in an oral form. Unfortunately some are also quite toxic to the liver. Orally administered AAS are very susceptible to first pass liver deactivation unless chemical molecular structures are altered to make them harder to deactivate. When an oral AAS is swallowed it enters the stomach where it is partially broken down and passed to the small intestines. The small intestines contain a group of enzymes called CYP-450 s. These enzymes begin to break down the AAS further in an attempt to deactivate it. The AAS is then absorbed through intestinal mucosa cells and transferred to the liver portal vein for further deactivation into inactive chemicals such as etiocholanone. These chemicals are then conjugated with glucuronic acid and excreted in urine. Up to 100% of the original compound can be deactivated in this process which is known as first pass deactivation. 

It has now been established that in common with many other glu-curonides, bilirubin glucuronide can be synthesized in the adult rat, rabbit, mouse, and guinea pig liver by the enzymatic transfer of glucuronic acid from uridine diphosphate glucuronic acid to an acceptor substance, namely, bilirubin (Fig. 3) (B17, G5, L3, L5, S8). The transferring enzyme (glucuronyl transferase) has been shown by Schmid et al. 

There are no adequate data to evaluate whether pharmacokinetics of DEHP in children are different from adults. It is not known whether DEHP (or metabolites) can cross the placenta in humans, although it has been detected in breast milk (FDA 200 lh). Studies in animals have shown that DEHP (or metabolites) crosses the placenta and can be transferred to offspring via mother s milk however, quantitative data are lacking. There is no information to evaluate whether metabolism of DEHP is different in children than in adults since the specific phase I enzymes involved in DEHP metabolism have not been identified. It is known that phase II metabolism involves conjugation with glucuronic acid, but the specific isoform of glucuronosyltransferase is not known. 

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