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Nicotinamide adenosine dinucleotide phosphate oxidase (NADPII) is involved in the
respiratory burst generating Oz- as a result of phagocytic triggering (Segal 1989). The Oz-
produced is a precursor of other reactive oxygen species such as hydrogen peroxide (HzOz)
and hydroxyl radical (OH.). NADPH oxidase is produced primarily in
polymorphonucleocytes, monocytes and macrophages - all expendable cells in host defence.
It is membrane bound but has membrane and cytoplasmic subunits and is responsible for
defence against extracellular pathogens and engulfed organisms accessible to phagocytic
cells. Activation and priming occurs with INFI, PAF, GCSF, GMCSF, ILl, IL6, IL8, TNFa
and substance P. Activation can also occur with complement factor CF5a, chemotactic
factors, phorbol esters and fatty acids.
In comparison, iNOS can be induced in virtually all nucleated somatic cells and is responsible
for the defence against pathogens that survive and proliferate in the intracellular environment.
It lies within the cytoplasm and kills pathogens that enter the cells (Nathan 1992). When it
was realised that biosynthesis of NO was possible by the same cells, it meant that these cells
were capable of the production of a range of reactive potentially toxic oxynitrogen species
such as nitrosium (NO*), nitroxyl ions (NO-), NO2, and S-nitrosothiols (Stamler, Jaraki et al.
1992). However, although macrophages can have both NADPH oxidase and iNOS present,
O; and NO are not often simultaneously produced thus avoiding the formation of
perioxynitrite (ONOO-). They appear to be independently regulated although INFI induces
both enzyme systems. It may in part depend on the presence of L-arginine and the isomeric
form in which it is found (Ding, Nathan et al. 1988; Martin and Edwards 1993; Bastian and
Hibbs 1994).In isomerism the 'cis'form is when the two substituent groups are orientated in
the same direction, while the 'trans'form is when the substituents are oriented in opposing
directions. In the trans form, ONOO- undergoes homolytic cleavage to form highly reactive
molecules HO* and NOz which can produce significant and irreversible damage to microbes,
but also to host cells. However the cis form, ONOO- reilranges to form a non-toxic nitrate
and it may be that the conditions for formation of these cis and trans isomers are what
determine their formation in these cells.
3.4.5 Drugs and other agents that affect the isoenrymes and nitrtc oxide production
3.4.s (i) Drugs
Corticosteroids inhibit the expression of inducible but not constitutive forms of NOS. This
occurs at transcriptional level, with the ability to inhibit the induction of iNOS, but they are
ineffective once the enzyme is synthesised. There are no recognisable steroid responsive
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