Retinoids and Carotenoids in Dermatology PDF

Preface

There are numerous reasons for publishing a book that jointly focuses on retinoids and carotenoids and on their relevance in skin biology and dermatology. Retinoids (i.e., retinol and its analogs) and carotenoids are both chemically and biologically related; the latter molecules are all basically polyprenoids (i.e., consist of repeated isoprene units) and are more or less omnipresent in nature (1,2). Some carotenoids (principally beta-carotene) can be converted to retinoids in mammals and fishes via enzymatic cleavage, making them important precursors of vitamin A in the diet. Furthermore, both groups of compounds are characterized by the high number of synthetic derivatives that have appeared since the advance of organic chemistry in the 1940s. Yet, from a biologic and therapeutic standpoint, retinoids and carotenoids are often regarded as separate entities, probably because they are used for different indications and have profoundly different dose-response curves.

Retinoid therapy, in the form of high-dose oral vitamin A, was initiated in the 1940s for hyperkeratotic skin diseases, but was later abandoned for toxicity reasons. Following the identification of all-trans retinoic acid as an active metabolite of vitamin A in the 1950s and the production of new retinoid derivatives in the 1970s with better therapeutic ratios in animal tumor models, some of these compounds (notably isotretinoin and acitretin) have since become a sine qua non for dermatology, especially in the field of acne, psoriasis, and keratinizing disorders. Subsequent to the discovery of retinoic acid receptors and their role in transcriptional regulation of important genes in the 1980s, a whole new paradigm has arisen where the strategy is to design specific ligands for the various retinoid receptors, aiming at fine-tuning the transcription machinery to mitigate various pathogenic mechanisms. As a direct consequence, new drugs and new indications for retinoid therapy have appeared, such as the use of oral bexarotene (targretin) in cutaneous lymphoma and alitretinoin (9-cis retinoic acid) in chronic hand eczema (3), and targretin gel has been used to treat chronic hand dermatitis and alopecia areata. However, not all effects of retinoids are mediated by nuclear receptors, a fact that should not be overlooked when designing new drugs in this field.

Regrettably, throughout the process of developing new retinoids, toxicity problems (teratogenicity, etc.) have remained an insurmountable obstacle that necessitates strict precautions when prescribing oral formulations. Therefore, this book not only discusses the side effects and how to avoid them, but also focuses on useful knowledge about the pharmacology and various peculiarities of retinoid pharmacodynamics that underlie the untoward effects.

Carotenoids, on the other hand, are compounds that are much less toxic and are mainly known in human medicine for their antioxidant properties. They are prescribed by dermatologists to patients with various photosensitivity syndromes (e.g., protoporphyria), most often in the form of oral beta-carotene. Canthaxantin is another carotenoid that was popular in the 1980s as artificial skin pigmentation, but it was withdrawn from the market due to a hazardous accumulation in the retina after oral administration. More recently, a variety of other carotenoid molecules have been re-examined in the field of dermatology and may eventually emerge as approved drugs. Carotenoids are thought to play a significant part in the skin's natural antioxidant defense system and may also help prevent malignancy in other organs. This has led to an interest in monitoring the individual's carotenoid status, for example, by using such noninvasive techniques as Raman spectroscopy of the skin, showing a good correlation to the blood levels of carotenoids. Although the promising anti-tumor effects of carotenoids (and retinoids) originally observed in animal experiments have been somewhat disappointing when translated to the human situation, there are several indications that this may change in the future.

Although carotenoids in their capacity as lipid-soluble antioxidants and scavengers of free radicals seem to operate in human tissues mostly via non-genomic mechanisms, recent studies indicate that they may also affect more specific cellular functions. So, in this sense also, carotenoids and retinoids may again be merging and we may benefit from a combined approach when describing the mechanism of their action.

The primary objective of this book is to describe how retinoids and carotenoids function in the skin, and how they can be used as powerful agents to prevent and treat skin diseases. Although the emphasis of this book is on the clinical aspects of these compounds, several chapters are devoted to new basic research that is being done despite the adverse reactions that can especially characterize the retinoids. It goes without saying that this treatise is not strictly confined to dermatological aspects, but also describes important developments in other fields of retinoid and carotenoid research, especially in relation to cancer and immunology. Furthermore, the book provides a means for some readers to update their knowledge about biomedical issues outside the field of dermatology, such as general vitamin A nutrition, the role of antioxidants in aging, metabolic activation and degradation of polyprenoids, cellular signalling, inflammation, and the role of lipoproteins in atherosclerosis.

In organizing the book we included chapters written by internationally recognized authorities with widely different backgrounds, ranging from biochemistry and nutrition to molecular biology and clinical science. It is our hope that this broad approach attracts not only dermatologists, but also other clinicians and scientists with a general interest in retinoids, carotenoids, and the biology of the skin. We wish to express our sincere gratitude to all authors for their valuable contributions.