In vitro hepatic metabolism of a CYP3A-mediated drug, quinine, in Adelie penguins

Very little is known about Antarctic animals' ability to metabolise or deto xify xenobiotics. The activity of cytochromes P450 subfamily 3A (CYP3A) in Adelie penguin liver was studied by incubating penguin liver microsomes wit h a human CYP3A substrate, quinine, and results were compared with those fr om human liver microsomes. The mean maximum rate of metabolism (Vmax) for q uinine in penguin livers was approximately five times less (160 +/- 72 vers us 574 +/- 416 pmol/mg/min; P < 0.01), and the mean Km (substrate affinity) for the formation of quinine's major metabolite (3-hydroxyquinine) was sig nificantly greater than that observed in human livers (160 +/- 73 Versus 83 +/- 19 mu M; P < 0.01). The mean intrinsic clearance (Vmax/Km) was 1.1 +/- 0.4 mu l/min (penguin), i.e. sevenfold less than in human livers (7.4 +/- 5.9 mu l/min, P < 0.005), suggesting that penguins have much less ability t han humans to eliminate xenobiotics having a similar metabolic nature to qu inine (i.e. CYP3A substrates). 3-Hydroxyquinine formation in penguin liver was inhibited by specific CYP3A inhibitors, midazolam and troleandomycin, b ut not by other CYP inhibitors, indicating that quinine metabolism to 3-hyd roxyquinine in Adelie penguin liver is likely to be catalysed by a CYP isof orm resembling human CYP3A. Adelie penguin liver CYP isoforms could serve a s biomarkers for the impact of environmental pollution. (C) 1999 Elsevier S cience Inc. All rights reserved.