Presence and induction of drug metabolizing enzymes in rat bone marrow
Dresner, J.H.; Ibrahim, N.G.; Levere, R.D.
Research Communications in Chemical Pathology and Pharmacology 32(2): 281-298
1981
ISSN/ISBN: 0034-5164 PMID: 6787676 Document Number: 174234
Little information is available concerning the ability of the bone marrow to participate in the detoxification and biotransformation of drugs and environmental agents. Employing rat bone marrow cells, a phase I, cytochrome P-450 dependent enzyme, aminopyrine-N-demethylase and a phase II detoxification enzyme, UDP-glucuronyl transferase were studied. Using etiocholanolone as a substrate for UDP-glucuronyl transferase, a kinetic study indicated a Km of 0.0093 mM and a Vmax of 0.0087 pmol etiocholanolone-glucuronide formed/mg per min where bone marrow microsomes were used as a source of enzyme. These values are compared to UDP-glucuronyl transferase activity in rat liver microsomes which indicated a Km of 0.125 mM and a Vmax of 0.340 pmol etiocholanolone-glucuronide formed/mg per min. Aminopyrine-N-demethylase activity in bone marrow microsomes had a Km of 5.54 mM and a Vmax of 0.132 nmol HCOH formed/mg per h. The demethylase activity in rat liver microsomes had a Km of 0.61 mM and a Vmax of 16.13 nmol HCOH/mg per h. Pretreating rats with 3-methylcholanthrene caused a 155% increase in demethylase activity over that found in untreated bone marrow. The activity of UDP-glucuronyl transferase was detectable only after pretreatment with 3-methylcholanthrene. The higher Km of uninduced bone marrow demethylase as compared to that found in liver indicates that the bone marrow enzyme has a lower affinity for the substrate tested as compared to liver. The presence of UDP-glucuronyl transferase and aminopyrine-N-demethylase activities was demonstrated in rat bone marrow using a very sensitive method for their determination in marrow cells. The pattern of enzyme induction by 3-methylcholanthrene suggests that depression of hematopoietic cell function may depend, in certain instances, on the pharmacological microenvironment of these cells and their ability to respond to various inducers and xenobiotics by biotransformation and detoxification.