regulation of hepatic heme oxygenase by comp

HEME IRON PROTEINS AND PORPHYRIN ANALOGS 515

|92 REGULATION OF HEPATIC HEME OXYGENASE BY CoMP

Ramesh Chandra,Mukta Dhawan, and Rajni Department of Chemistry, University Delhi-llO007, India.

Malhotra of Delhi,

Vi tamin A p lays a s i g n i f i c a n t r o t e in m a i n t a i n i n g the f u n c t i o n a l i n t e g r i t y of

c e l l u l a r membrane and v a r i o u s subceL lu l a r o r g a n e l l e s , i t a l s o causes hemolys is of

e r y t h r o c y t e s , t he reby r e l e a s i n g hemoglobin. Recent s t u d i e s have shown tha t hepat~L

heme oxygenase system exerts potent degradative effects on microsomat cytochr~-~ne

P-450 and P-450 mediated drug metabolism (I). It has been proposed that cytochrc~ne

P.450 is e s s e n t i a l f o r the ca tabo l i sm of microso. '~[ heme and tha t heme COmlDour'*ds

se rve as s u b s t r a t e s f o r a microsomat system which is s i m i l a r to tha t i n v o l v e d in

drug metabo l ism. In t h i s i n v e s t i g a t i o n we have taken the advantage o f the a b i l i t y

of Cobalt chloride to decrease the microsomal content of cytochrotne P-650 and the

oxidative metabolism of drugs (2,3). Vitamin A when administered orally for two

days (I0,000 I.U.) to the neonates led to partial paralysis. However, when Virgin

A was administrated simultaneously #ith CoMP (Cobalt Mesoporphyrin), no paralysis

was observed. Our results demonstrates a striking ability of Co~P to enhance the

r a t e o f Heme o x i d a t i o n by l i v e r c e l l s in the presence ~f V i tamin A. We have atsc

e £ t a b l i s h e d t ha t t he re is a d i s s o c i a t i ~ q of t h i s process from the hepa t i c con ten t

of cytochrome P-450. These f i n d i n g thus d e f i n e a novel ar,d po ten t b i o l o g i c a l ac t~o r

o f CoMP in a s s o c i a t i o n w i th V i tamin A on the ra t l i v e r and imp l i es the e x i s t e n c e o{

a P-450 independent microsoma[ enzyme system f o r the o x i d a t i v e c a t a b o l i s m of bane_

which is d i s t i n c t f rom tha t concerned wi th drug o x i d a t i o n . Meme Oxygenase a c t i v i t y

and s p e c i f i c a c t i v i t y i s induced s i g n i f i c a n t l y , mere than 6 f o l d s w i th CoMP as

compared to o r a l t r ea tmen t o f V i tamin A a lone .

EFFECT OF VITAMIN A AND CoMP ON HO ACTIVITY (nmol/untts)

ENZYME ACTIVITY & $PECI?IC ACTIVITY 25

15

0 5

CONTROL ~TA~IN A %qT A-CoMP EFFECT ON NEONATAL WISTER ~ATS

Ser te s ] ~ Ser~es 2

I. R. Tenhunen, H.S. Marver, and R. Schmid, J.Biol. Chem., 244(23), 6388-94 (1969)

2. R. 8eri and R. Chandra, Drug Metabolism Reviews, ZS(1&2), 49-152 (1993)

3. Li Zhang and I. Guarente, EMBO, 14(2), 313-320 (1995)