REQUIREMENT FOR OMEGA AND (OMEGA - 1 )-HYDROXYLATIONS OF FATTY ACIDS BY HUMAN CYTOCHROMES P450 2E1 AND 4A11

Human liver microsomes and recombinant human P450 have been used as enzyme source in order to better understand the requirement for the optimal rate of v and ( v -1)-hydroxylations of fatty acids by cytochromes P450 2E1 and 4A. Three parameters were studied: alkyl chain length, presence and configuration of double bond(s) in the alkyl chain, and involvement of carboxylic function in the fatty acid binding inside the access channel of P450 active site. The total rate of metabolite formation decreased when increasing the alkyl chain length of saturated fatty acids (from C12 to C16), while no hydroxylated metabolite was detected when liver microsomes were incubated with stearic acid. However, unsaturated fatty acids, such as oleic, elaidic and linoleic acids, were v and ( v -1)-hydroxylated with an efficiency at least similar to palmitic acid. The ( v -1)/ v ratio decreased from 2.8 to 1 with lauric, myristic and palmitic acids as substrates, while the reverse was observed for un- saturated C18 fatty acids which are mainly v -hydroxylated, except for elaidic acid showing a metabolic profile quite similar to those of saturated fatty acids. The double bond configuration did not significantly modify the ability of hy- droxylation of fatty acid, while the negatively charged car- boxylic group allowed a configuration energetically favour- able for v and ( v -1)-hydroxylation inside the access channel of active site. —Adas, F., J.P. Salaun, F. Berthou, D. Picart, B. Simon, and Y. Amet. Requirement for v and ( v - 1)-hydroxylations of fatty acids by human cytochromes P450 2E1 and 4A11. J. Lipid Res. 1999. 40: 1990-1997.