1999 Volume 14 Issue 2 Pages 139-147
Cytochrome P450s (P450s) in the CYP4 family metabolize both drugs and endogenous substances such as arachidonic acid and prostaglandins. To clarify the biological roles of these P450s, they were purified by HPLC with an ion-exchange column and a hydroxylapatite column. All purified P450s metabolized lauric acid at the co-position. CYP4A and 4F metabolized arachidonic acid to ω-hydroxyarachidonic acid (20-HETE) which is reported to be a potent vasoconstrictor. On the contrary, CYP4B1 activated aromatic amines such as 3, 3-dichlorobenzidine and 2-naphthylamine to mutagenic substances. Antibodies against these P450s were prepared and localization of these P450s was investigated by Western blotting. These P450s revealed tissue-specific expression. CYP4A was present in the liver and kidney of human and experimental animals and CYP4B1 in the lung and bladder. CYP4F was present in the liver. Regulation of rat CYP4A2 was investigated. CYP4A2 was a male-dominant form in rat kidney and induced by diabetes. Castration decreased the CYP4A2 level in the kidney of male rats and testosterone increased CYP4A2 in the kidneys of both castrated male and untreated female rats, demonstrating that CYP4A2 is regulated directly by androgen. Human renal P450 was purified from renal microsomes and its cDNA was cloned with CYP4A2 cDNA as a probe. Human renal P450 was designated to CYP4A11 which had an identical N-terminal amino acid sequence with purified human P450 and similar characteristics as rat CYP4A2.
