Cholesterol-5,6-epoxides: Chemistry, biochemistry, metabolic fate and cancer

Abstract

In the nineteen sixties it was proposed that cholesterol might be involved in the etiology of cancers and cholesterol oxidation products were suspected of being causative agents. Researchers had focused their attention on cholesterol-5,6-epoxides (5,6-ECs) based on several lines of evidence: 1) 5,6-ECs contained an oxirane group that was supposed to confer alkylating properties such as those observed for aliphatic and aromatic epoxides. 2) cholesterol-5,6-epoxide hydrolase (ChEH) was induced in pre-neoplastic lesions of skin from rats exposed to ultraviolet irradiations and ChEH was proposed to be involved in detoxification processes like other epoxide hydrolases. However, 5,6-ECs failed to induce carcinogenicity in rodents which ruled out a potent carcinogenic potential for 5,6-ECs. Meanwhile, clinical studies revealed an anomalous increase in the concentrations of 5,6β-EC in the nipple fluids of patients with pre-neoplastic breast lesions and in the blood of patients with endometrious cancers, suggesting that 5,6-ECs metabolism could be linked with cancer. Paradoxically, ChEH has been recently shown to be totally inhibited by therapeutic concentrations of tamoxifen (Tam), which is one of the main drugs used in the hormonotherapy and the chemoprevention of breast cancers. These data would suggest that the accumulation of 5,6-ECs could represent a risk factor, but we found that 5,6-ECs were involved in the induction of breast cancer cell differentiation and death induced by Tam suggesting a positive role of 5,6-ECs. These observations meant that the biochemistry and the metabolism of 5,6-ECs needed to be extensively studied. We will review the current knowledge and the future direction of 5,6-ECs chemistry, biochemistry, metabolism, and relationship with cancer.

Introduction

Cholesterol is a tetracyclic lipid of growing biological importance since its discovery by François Poulletier de la Salle in 1758 and was first named cholesterine by Christian Chevreul in 1815 [1]. Since the last century cholesterol is known to be subject to oxidation leading to the formation of mono- or poly-oxygenation products called oxysterols. The main functional groups containing oxygen atoms are epoxides, ketones, hydroxyl and peracids [2]. Oxysterols are produced through enzymatic reactions reflecting the existence of a metabolic pathway and are also produced by autoxidation through non-enzymatic mechanisms, which are associated with inflammatory-linked pathologies [2]. It is however interesting to note that most oxysterols can be produced through chemical reactions and were discovered by chemists and biochemists before the enzymes responsible for their biosynthesis were characterized [3], [4], [5]. Among these oxysterols, 5,6-ECs have stimulated the interest of researchers some years after the photo-oxidation products of cholesterol were suspected to be involved in photo-carcinogenesis [6]. Because of the presence of an oxirane group, it was supposed that 5,6-ECs could be electrophilic and behave like alkylating agents with direct carcinogenic properties. Recent data from literature ruled out that 5,6-ECs could be direct alkylating substances [7] and provides evidence that 5,6-ECs may be involved in physiological processes that result in metabolites with tumor promoter properties as well as to the production of steroidal alkaloids which are anti-oncogenic.