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Interaction of phthalazines with molybdenum hydroxylases. Phthalazine and its 1-substituted derivatives as substrates, inhibitors and inducers of aldehyde oxidase and xanthine oxidase, both in vitro and in vivo.
Johnson, Christine
Johnson, Christine
Publication Date
2009-10-02T15:07:23Z
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The University of Bradford theses are licenced under a Creative Commons Licence.
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Institution
University of Bradford
Department
Postgraduate School of Studies in Pharmaceutical Chemistry.
Awarded
1983
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Abstract
The interaction of the 2,3-diazanaphthalene, phthalazine and its
1-substituted derivatives with the molybdenum hydroxylases, aldehyde
oxidase and xanthine oxidase, has been investigated both in vivo and
/Ok in vitro.
Metabolic studies, carried out by treating rabbits with both cold
and
14C-labelled
phthalazine, have shown that this compound is extensively
metabolised in vivo, the major metabolite being a glucuronide conjugate.
Very little unchanged phthalazine or its molybdenum hydroxylase
mediated oxidation product 1-hydroxyphthalazine were excreted in the
urine.
Pretreatment of rabbits with phthalazine or 1-hydroxyphthalazine
had no effect upon the activity of the microsomal monooxygenases but
caused a significant increase in the specific activities of both
aldehyde oxidase and xanthine oxidase.
Determination of the molybdenum content of purified aldehyde
oxidase fractions using electrothermal atomic absorption spectroscopy
has confirmed that an increase in the molybdenum content of the enzyme
fraction accompanies the increase in activity.
A qualitative assessment of purified aldehyde oxidase fractions
using iso-electric focusing has indicated that this enzyme may be
composed of 2 or 3 active variants and following pretreatment with
either phthalazine or 1-hydroxyphthalazine a further band of enzyme
activity is apparent on the electropherogram.
The Km value for phthalazine is significantly reduced with enzyme
prepared from phthalazine treated rabbits, indicating that a form of the
enzyme with a high affinity for phthalazine may have been induced.
1-Hydrazinophthalazine (Hydralazine) and two other hydrazine
substituted N-heterocycles, endralazine and 1-hydrazinoisoquinoline have
been shown to exert a potent progressive inhibition of aldehyde oxidase
in vitro, effective only in the presence of substrate, but are inactive
towards xanthine oxidase.
In addition, administration of hydralazine to rabbits results in a
significant reduction in liver aldehyde oxidase activity. Investigations
into the interaction of some of the metabolites of hydralazine with
aldehyde oxidase in vitro suggest that hydralazine is also the
inhibiting species in vivo.
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Thesis
Qualification name
PhD