Roles of Cytochrome P450 in Development

Abstract

Cytochrome P450 (CYP) forms are ubiquitous in nature, appearing in almost all phyla, with many forms appearing in any organism. About 50 different forms have been identified in man, and some of these are found in the embryo, some showing temporal dependence. Many of the forms of cytochrome P450 present in one species have homologues in other species. For example, CYP1A2 is present in many species, including man, rabbits, rodents, fish and fowl. The amino acid sequence identity of these homologues is often in excess of 70%. CYP26, too, has more than 61% identity in amino acid sequence between fish, fowl and mammals. In view of the high degree of conservation of sequence as well as of enzymatic activities, it is only reasonable to assume that such strong conservation of sequence also reflects a conservation of function. Since the 'xenobiotic metabolizing' enzymes predate the production of the many xenobiotics they are known to metabolize, perhaps it is reasonable to consider endobiotics as natural substrates for their metabolism. Of the identified forms of cytochrome P450 that are present in embryonic tissue, we consider the possibility that they serve the organism in support of morphogenesis of the embryonic tissue. These forms may either function to generate morphogenic molecules or to keep regions free of them, thereby creating temporal and spatial regions of morphogen action and supporting region-specific changes in cells. One known morphogen, retinoic acid, has the enzymes retinal dehydrogenase (RALDH) and CYP26 maintaining its actions, the former responsible for its generation and the latter for its elimination. Another form of cytochrome P450, CYP1B1 appears also to be involved in differentiation of tissue, with its absence resulting in primary congenital glaucoma. However, the nature of the morphogen it may maintain still remains to be elucidated.