CONSEQUENCES OF CHALLENGE INFECTIONS WITH FASCIOLA-HEPATICA ON RAT-LIVER P450-DEPENDENT METABOLISM OF SEX-HORMONES

The effect of single or repetitive fluke-infections on rat liver steroid hormone metabolism was studied. Fascioliasis was induced by oral administration of 20 metacercariae of Fasciola hepatica to rats, by week-6 (mono-infected) or 12 and 6 (bi-infected), or 12, 9 and 6 (tri-infected) before killing. Total microsomal cytochrome P450 and P450 isoenzymes were measured spectrophotometrically and by Western-blot analysis, respectively. Progesterone and testosterone metabolism were quantified by normal phase high performance liquid chromatography. In control rats, progesterone and testosterone were mainly converted to 2 alpha- and 16 alpha-hydroxymetabolites. In the liver of mono-infected rats, hepatic cytochrome P450 was significantly decreased by 36-64% whereas the expression of all investigated isoenzymes was decreased by 36-82% with the exception of the unchanged P4502E1. 16 alpha- and 2 alpha-hydroxylations of progesterone and testosterone were significantly decreased by 50-90%, these decreases were correlated with those of P4502B1/2 and P4502C11 isoenzymes, respectively. In bi- and tri-infected rats, steroid hormones were metabolized similarly to control rats. The return of steroid drug metabolizing enzyme activities to control level could be related to the immune response associated to the development of the animal resistance to the parasitic infection.