Particular cytochrome P450-dependent steroid metabolism: a new class of mouse liver tumor markers

Abstract

An altered pattern of cytochrome P450-dependent micro somal steroid metabolism was identified in female mouse liver tumors induced by 5,9-dimethyldibenzo[c, g]carbazole a potent organo-specific liver carcinogen. These tumor tissues were compared to extratunioral liver parenchyme, to normal, fetal and neonatal livers and to spontaneous liver tumors, the frequency of which is very low in the highly hybridized mouse strain (XVIInc/Z) used for liver tumonlgenesis. Cytochrome P-450-dependent steroid hydroxylase activities were measured by the identification and quantification of four mono hydroxyprogesterone and eight monohydroxytestosterone metabolites. In contrast to a general decrease (50%) of total P-450 in tumor microsomes, the individual steroid hydroxyl ases were regulated differentially. Progesterone 16α- and testosterone 6α 6β-, 7α- and l6α-hydroxylase activities were decreased 50%, and more, whereas progesterone and testosterone 16α-hydroxylase activities were raised 3–4 times with regard to microsomal protein content and 6–7 times with regard to total P-450. Consequenfly the most prominent feature of the steroid metabolism by tumor-borne microsomes is the hydroxylation at the 15α-position. Furthermore, minor testosterone 2- and l5β-hydroxylase activities showed equally an increase of ∼4 tunes (8 times with regard to total P-450). The observed new tumoral pattern of P-450-dependent microsomal steroid metabolism appearing characteristically in spontaneous and chemically induced liver tumors indicates that particular P-450 enzymes are strongly expressed in mouse liver tumors. These enzymes may be used as markers for early stages in liver tumorigenesis.