Review
CYP2S1: A short review

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Abstract

A new member of the cytochrome P450 superfamily, CYP2S1, has recently been identified in human and mouse. In this paper, we review the data currently available for CYP2S1. The human CYP2S1 gene is located in chromosome 19q13.2 within a cluster including CYP2 family members CYP2A6, CYP2A13, CYP2B6, and CYP2F1. These genes also show the highest homology to the human CYP2S1. The gene has recently been found to harbor genetic polymorphism.

CYP2S1 is inducible by dioxin, the induction being mediated by the Aryl Hydrocarbon Receptor (AHR) and Aryl Hydrocarbon Nuclear Translocator (ARNT) in a manner typical for CYP1 family members. In line with this, CYP2S1 has been shown to be inducible by coal tar, an abundant source of PAHs, and it was recently reported to metabolize naphthalene. This points to the involvement of CYP2S1 in the metabolism of toxic and carcinogenic compounds, similar to other dioxin-inducible CYPs.

CYP2S1 is expressed in epithelial cells of a wide variety of extrahepatic tissues. The highest expression levels have been observed in the epithelial tissues frequently exposed to xenobiotics, e.g., the respiratory, gastrointestinal, and urinary tracts, and in the skin. The observed ubiquitous tissue distribution, as well as the expression of CYP2S1 throughout embryogenesis suggest that CYP2S1 is likely to metabolize important endogenous substrates; thus far, retinoic acid has been identified.

In conclusion, CYP2S1 exhibits many features of interest for human health and thus warrants further investigation.

Section snippets

Identification of CYP2S1 in human and mouse

Cytochrome P450 (CYP) enzymes are involved in the oxidative metabolism of many endogenous molecules, such as steroids, fatty acids, eicosanoids, and retinoids, thereby participating in the maintenance of the body homeostasis (reviewed, e.g., by Nebert, 1991, Lewis, 2004). They also play a major role in the biotransformation of numerous exogenous compounds (xenobiotics). These include a wide range of important pharmacological drugs, such as antidepressants, neuroleptics, lipophilic

Regulation, induction, and metabolism

Many of the CYPs are not expressed constitutively, but are induced upon exposure to chemical compounds. The inducers are themselves usually substrates for these enzymes, thereby regulating their own biotransformation.

Tissue distribution of CYP2S1 expression

A majority of CYPs have their highest expression in the liver, which has a dominant role in the clearance of foreign compounds. However, many CYPs are also expressed in tissues other than the liver (Hukkanen et al., 2002, Ding and Kaminsky, 2003). Expression in the extrahepatic tissues may be of significance for the metabolism of exogenous substances, since these tissues are the major route of exposure, and thus also the potential target for harmful effects of the metabolites produced (Pelkonen

CYP2S1 expression during embryogenesis

There is growing evidence that some members of the CYP superfamily could be involved in the regulation of basic developmental processes such as pattern formation, morphogenesis, cell differentiation, and growth (Stoilov et al., 2001). As retinoids are known to be crucial for embryonic development (reviewed by Marill et al., 2003), those CYPs that are known to the participate in metabolism of retinoids, e.g., CYP1B1, CYP26, and now also CYP2S1, are of especial interest (Stoilov, 2001, Stoilov et

Genetic polymorphism of CYP2S1

The wide individual variation in metabolic capacity detected for many CYP enzymes may influence therapeutic efficacy and toxic side effects of drugs as well as individual susceptibility to chemical carcinogenesis (Raunio et al., 1995, Ingelman-Sundberg et al., 1999). Such variability has been found to be partly genetically determined. In fact, a majority of the CYP genes exhibit genetic polymorphisms (reviewed by Ingelman-Sundberg, 2004). In particular, many members of the CYP2 family, such as

Conclusions

CYP2S1 gene is a recently identified member of the CYP2 family, located on human chromosome 19q at the distal end of a cluster of CYP2 family members CYP2A6, CYP2A13, CYP2B6, and CYP2F1. Despite apparently sharing a common ancestor and sequence homology with other CYP2 family members, CYP2S1 exhibits many features that have been thought to be characteristic to the CYP1 family members, such as dioxin-inducibility mediated by AHR and ARNT. Furthermore, the expression pattern of CYP2S1 has been

Note added in proof

While this paper paper was in press, high expression of CYP2S1 was reported to be associated with poor prognosis in colorectal cancer (Kumarakulasingham et al., 2005).

Acknowledgments

Our work was financially supported by the Academy of Finland (grant no. 52276), the Work Environment Fund (grant no. 100389), and NIH Grant RO1CA28868 and Underrepresented Minority Supplement S1 to this grant (SR).

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