Læknablaðið : fylgirit - 01.06.1996, Page 12

12
LÆKNABLAÐIÐ 1996; 82/FYLGIRIT 31
Gastroenterology in the
new millennium
Ingvar Bjarnason
King's College School of Medicine & Dentistry. De-
partment of Clinical Biochemistry.
Advances in clinical gastroenterology liave been
rather slow in the last decade. However, a number
of recent developments in molecular biology seem
destined to be translated into clinical practice in the
next few years with major implications. Here I will
touch on two aspects of research which is already
posed to change the face of gastroenterology.
The adverse effects of NSAIDs, effective for con-
trol of joint pain and inflammation, prescribed in
abundance by rheumatologists and general physi-
cians, account for some 10-30% of gastroenterolog-
ical referrals. Five years ago it became evident that
there were two forms of cyclo-oxygenase (Cox),
namely constitutively expressed Cox-1 and Cox-2
which is specifically expressed at sites of inflamma-
tion by the presence of soluble mediators of in-
flammation, etc. It is then suggested that NSAID-
induced inhibition of Cox-1 accounts for their side
effects whilst inhibition of Cox-2 might account for
their desired therapeutic effect. A number of bi-
ological observations are consistent with these sug-
gestions. The genes coding for Cox-1 & 2 are on
separate chromosomes and well preserved in differ-
ent species. The Cox-1 gene has a simple regulation
of expression whilst the Cox-2 gene is more complex
with a TATA box and regions containing a number
of well known sequences for expression- stimula-
tion, in keeping with its inducibility. The Cox-1 & 2
enzymes have identical rates of activity in respect of
affinity and specificity for its major substrate arachi-
donic acid. Cox-1 & 2 have a 70-80% homology in
respect of amino acid sequences. The three dimen-
sional structure of Cox shows 3 main themes. A
catalytic module which has the two separate active
sites; a Cox domain and a peroxidase domain and
which does not differ significantly between Cox-1
and 2. Secondly a EGF module of unknown function
and lastly a membrane binding region which differs
between Cox-1 & 2. It is the characteristics of the
membrane binding domain which determines the
subcellular location of Cox-1 & 2 in the endoplasmic
reticulum and nuclear membrane, respectively.
From its anchorage in the lipid bi-layer there is a
narrow hydrophilic channel which leads to the active
sites of Cox-1 & 2 (a tyrosine which facilitates hydro-
gen removal from arachidonic acid).
Conventional NS^IDs, all of which (apart from
piroxicams) have a carboxylic group, bind to argi-
nine (position 120 and 106, respectively) and thereby
effectively block the access of arachidonic acid to
the active site accounting for their action. Aspirin on
the other hand acetylates a serine residue (position
530). Selective substitution of arginine and serine
with other amion-acids specifically abolishes the an-
tiinflammatory activity of NSAIDs and aspirin, re-
spectively. The three dimensional structure of Cox-1
& 2 (Cox-peroxidase domain) differs only in respect
of the width of the hydrophobic channel, Cox-2
being broader. This is, however, associated with
profound differences in the relative affinity of
NSAIDs for Cox-1 & 2. Indomethacin, piroxicam,
etc. have preferential affinity for Cox-1, diclofenac,
naproxen, 6-MNA and meloxicam have roughly
equal affinity for the two isoforms or slightly greater
affinity for Cox-2. Prior to elucidation of the three
dimensional structure of the Cox enzymes there was
a group of drugs, with a similar chemical structure,
which appeared anti- inflammatory without the ad-
verse effects of conventional Cox-1 inhibitors. We
now know that these are the highly specific Cox-2
inhibitor which have a 100 to 1000 greater affinity for
Cox-2 than Cox-1. Introduction of the Cox-2 selec-
tive NSAIDs into clinical practice was initially ham-
pered by the lack of confidence and knowledge of
action of these drugs. The problem facing the phar-
maceuticals is now not so niuch in developing new
highly specific Cox-2 inhibitors, there are virtually
hundreds that have been specifically designed, but