Dosage prescribing and plasma oxipurinol levels in patients receiving allopurinol therapy

Beedham

2005

Pharmacology

Aromatic aldehydes are good substrates of aldehyde dehydrogenase activity but are relatively poor substrates of aldehyde oxidase and xanthine oxidase. However, the oxidation of xenobiotic-derived aromatic aldehydes by the latter enzymes has not been studied to any great extent. The present investigation compares the relative contribution of aldehyde dehydrogenase, aldehyde oxidase and xanthine oxidase activities in the oxidation of isovanillin in separate preparations and also in freshly prepared and cryopreserved liver slices. The oxidation of isovanillin was also examined in the presence of specific inhibitors of each oxidizing enzyme. Minimal transformation of isovanillin to isovanillic acid was observed in partially purified aldehyde oxidase, which is thought to be due to residual xanthine oxidase activity. Isovanillin was rapidly metabolized to isovanillic acid by high amounts of purified xanthine oxidase, but only low amounts are present in guinea pig liver fraction. Thus the contribution of xanthine oxidase to isovanillin oxidation in guinea pig is very low. In contrast, isovanillin was rapidly catalyzed to isovanillic acid by guinea pig liver aldehyde dehydrogenase activity. The inhibitor studies revealed that isovanillin was predominantly metabolized by aldehyde dehydrogenase activity. The oxidation of xenobiotic-derived aromatic aldehydes with freshly prepared or cryopreserved liver slices has not been previously reported. In freshly prepared liver slices, isovanillin was rapidly converted to isovanillic acid, whereas the conversion was very slow in cryopreserved liver slices due to low aldehyde dehydrogenase activity. The formation of isovanillic acid was not altered by allopurinol, but considerably inhibited by disulfiram. It is therefore concluded that isovanillin is predominantly metabolized by aldehyde dehydrogenase activity, with minimal contribution from either aldehyde oxidase or xanthine oxidase.

Section: Discussionmentioning

confidence: 99%

Section: Metabolism Of Isovanillin With Freshly Prepared and Cryopresmentioning

confidence: 99%

Metabolism of Isovanillin by Aldehyde Oxidase, Xanthine Oxidase, Aldehyde Dehydrogenase and Liver Slices

Beedham

2005

Pharmacology

“…Incubations with freshly prepared liver slices were also performed in the presence of inhibitors. The inhibitors used were isovanillin for aldehyde oxidase activity [13,14], allopurinol for xanthine oxidase activity [29] and disulfiram for aldehyde dehydrogenase activity [30,31]. Aliquots (0.2 ml) were removed at t= 0 min and at various time intervals, added to 0.1 ml of 3.6 % perchloric acid and centrifuged for 2.5 min at maximum speed on a Beckman microfuge B.…”

Section: Incubation Conditions With Liver Slicesmentioning

confidence: 99%

Enzymatic Oxidation of Vanillin, Isovanillin and Protocatechuic Aldehyde with Freshly Prepared Guinea Pig Liver Slices

Beedham

2005

Cell Physiol Biochem

Background/Aims: The oxidation of xenobiotic-derived aromatic aldehydes with freshly prepared liver slices has not been previously reported. The present investigation compares the relative contribution of aldehyde oxidase, xanthine oxidase and aldehyde dehydrogenase activities in the oxidation of vanillin, isovanillin and protocatechuic aldehyde with freshly prepared liver slices. Methods: Vanillin, isovanillin or protocatechuic aldehyde was incubated with liver slices in the presence/absence of specific inhibitors of each enzyme, followed by HPLC. Results: Vanillin was rapidly converted to vanillic acid. Vanillic acid formation was completely inhibited by isovanillin (aldehyde oxidase inhibitor), whereas disulfiram (aldehyde dehydrogenase inhibitor) inhibited acid formation by 16% and allopurinol (xanthine oxidase inhibitor) had no effect. Isovanillin was rapidly converted to isovanillic acid. The formation of isovanillic acid was not altered by allopurinol, but considerably inhibited by disulfiram. Protocatechuic aldehyde was converted to protocatechuic acid at a lower rate than that of vanillin or isovanillin. Allopurinol only slightly inhibited protocatechuic aldehyde oxidation, isovanillin had little effect, whereas disulfiram inhibited protocatechuic acid formation by 50%. Conclusions: In freshly prepared liver slices, vanillin is rapidly oxidized by aldehyde oxidase with little contribution from xanthine oxidase or aldehyde dehydrogenase. Isovanillin is not a substrate for aldehyde oxidase and therefore it is metabolized to isovanillic acid predominantly by aldehyde dehydrogenase. All three enzymes contribute to the oxidation of protocatechuic aldehyde to its acid.

“…Homovanillamine incubations with freshly prepared liver slices were also performed in the presence of the inhibitors, isovanillin for aldehyde oxidase [6,7], allopurinol for xanthine oxidase [26] and disulfiram for aldehyde dehydrogenase activity [27,28]. For comparison reasons, the results on the effect of inhibitors in freshly prepared liver slices have been normalized per 100 mg of liver.…”

Section: Incubation Conditions With Freshly Prepared and Cryopreservementioning

confidence: 99%

Metabolism of Homovanillamine to Homovanillic Acid in Guinea Pig Liver Slices

2005

Cell Physiol Biochem

Background/Aims: Homovanillamine is a biogenic amine that it is catalyzed to homovanillyl aldehyde by monoamine oxidase A and B, but the oxidation of its aldehyde to the acid derivative is usually ascribed to aldehyde dehydrogenase and a potential contribution of aldehyde oxidase and xanthine oxidase is usually ignored. Methods: The present investigation examines the metabolism of homovanillamine to its acid derivative by concurrent incubation with monoamine oxidase and aldehyde oxidase. In addition, the metabolism of homovanillamine in freshly prepared and cryopreserved liver slices is examined and the relative contribution of aldehyde oxidase, xanthine oxidase and aldehyde dehydrogenase activity by using specific inhibitors of each oxidizing enzyme is compared. Results: Homovanillamine was rapidly converted mainly to homovanillic acid when incubated with both momoamine oxidase and aldehyde oxidase. Homovanillic acid was also the main metabolite in the incubations of homovanillamine with freshly prepared or cryopreserved liver slices, via the intermediate homovanillyl aldehyde. The acid formation was 70-75 % inhibited by disulfiram (specific inhibitor of aldehyde dehydrogenase), whereas isovanillin (specific inhibitor of aldehyde oxidase) inhibited acid formation to a lesser extent (50-55 %) and allopurinol (specific inhibitor of xanthine oxidase) had almost no effect. Conclusions: Homovanillamine is rapidly oxidized to its acid, via homovanillyl aldehyde, by aldehyde dehydrogenase and aldehyde oxidase with little or no contribution from xanthine oxidase.