Regulation of cytochrome P450 expression by sphingolipids

Sphingolipids modulate many aspects of cell function, including the express ion of cytochrome P450, a superfamily of heme proteins that participate in the oxidation of a wide range of compounds of both endogenous (steroid horm ones and other lipids) and exogenous (e.g. alcohol, drugs and environmental pollutants) origin. Cytochrome P450-2C11 (CYP 2C11) is down-regulated in r esponse to interleukin-1 beta (IL-1 beta), and this response involves the h ydrolysis of sphingomyelin to ceramide as well as ceramide to sphingosine, and phosphorylation of sphingosine to sphingosine 1-phosphate. Activation o f ceramidase(s) are a key determinant of which bioactive sphingolipid metab olites are formed in response to IL-1 beta. Ceramidase activation also appe ars to account for the loss of expression of CYP 2C11 when hepatocytes are placed in cell culture, and the restoration of expression when they are pla ted on Matrigel; hence, this pathway is influenced by, and may mediate, int eractions between hepatocytes and the extracellular matrix. Recent studies using inhibitors of sphingolipid metabolism have discovered that sphingolip ids are also required for the induction of CYP 1A1 by 3-methylcholanthrene, however, in this case, the requirement is for de novo sphingolipid biosynt hesis rather than the turnover of complex sphingolipids. These findings ill ustrate how changes in sphingolipid metabolism can influence the regulation of at least several isoforms of cytochrome P450. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.