Editorial [ Environmental Impacts on Enzymes Involved in Drug and Steroid Metabolism Guest Editor: R.H. Waring ]

Although there has been much effort in recent years to unravel the complications of pharmacogenetics in drug metabolism, impacts which are ‘environmental’ in the widest sense are also important and have been relatively neglected. Typically, they underlie at least 20-30%of the variation seen in any metabolic pathway within a human population but because they often do not impact on the genome, the effects are less easy to recognise. The input is multifactorial and often comes from surprising sources, including diet [1], indoor air [2], concomitant drug therapy [3], pesticides [4] industrial accidents [5] urban dust particulate matter [6] and medical devices [7]. Some environmental contributions are more obvious than others or have clear therapeutic implications- for instance the inhibition of CYP 3A4 by fruit juices and grapefruit furanocoumarins has been investigated and shown to affect the gastrointestinal first-pass metabolism of certain statins as well as other drugs such as warfarin and felodipine [8,9]. Aromatase (CYP2C19) is an isoform of cytochrome P-450 which converts androgens such as testosterone to oestrogens such as oestradiol by catalysing the formation of the aromatic (phenolic) ring which is the distinguishing feature of the female steroid hormones. This pathway is a metabolic bottleneck since it appears to be the only means of synthesising oestrogens in mammals. Its inhibition is used in therapy for breast cancers which are usually oestrogen-dependent [10]; drugs such as anastrozole which are aromatase inhibitors are now in routine use [11]. However, like many CYP isoforms, aromatase is inhibited by dietary components at levels which may be physiologically relevant [12]. The effects of environmental modulation of CYP isoforms and glucuronyltransferases have recently been described in several papers [12,13,14]; both these pathways are central to drug metabolism but can be modulated by components, often including flavonoids, from Brassica, Cruciferae, Allium and other plant families. Dietary indoles and flavonoids can activate CYP1A expression either by direct ligand interaction with the arylhydrocarbon receptor (AhR) or by increasing the interaction of the AhR with xenobiotic response elements in CYP1A1 and other target genes. Interactions with pharmacogenetic variation can also occur [5,15]; cruciferae interact with the glucuronyltransferase polymorphism UGT1A1*28 which has decreased UGT1A1 promoter activity due to 7 thymine-adenine (TA) repeats although no interaction was seen with individuals with the wild-type 6 (TA) repeats [15]. The contributions of dietary and environmental factors to the activities of other pathways have been less well-explored and this collection of articles focuses on a range of enzymes which although they are not ‘the usual suspects’ are nevertheless main stream. Flavin monoxygenase (FMO-3) catalyses the conversion of trimethylamine, which smells of fish, to its N-oxide which does not [16]. Inhibition of this enzyme may therefore affect the social interactions of the individuals concerned and inspection of web-sites devoted to perception of body odour (eg those for trimethylaminuria/‘fish odour syndrome’) shows that this can be a major problem. The COMT (catechol-Omethyltransferase) isoforms act as methylating agents using S-adenosylmethionine as donor. Oestrogens are converted to 4-catechol oestrogens which can be metabolised to their methoxy derivatives by COMT or oxidised to catechol oestrogen-3,4-quinone metabolites. This process impacts on carcinogenesis as the oestrogen quinone metabolites are believed to react with DNA to form depurinating adducts and to induce mutations. Reduced activity of COMT might therefore be a risk factor for oestrogen-sensitive tumours and reduced expression of COMT in breast tissue has been linked with a higher susceptibility to breast cancer [17]. Inhibition of the COMT enzymes by a range of common industrial pollutants may therefore be an aetiological factor in this increasingly common disease. Recent research has shown that many persistent organic pollutants (POPS), including PCB metabolites and plasticisers, can inhibit the various isoforms of the sulphotransferase (SULT) enzymes [18]. In general, the addition of sulphate is a pathway for detoxication/inactivation and endogenous compounds such as dopamine and oestrogen give metabolites which are more water-soluble and no longer active at the receptors. Many, although not all, drug sulphate conjugates (Minoxydil is an exception) are similarly inactive pharmacologically so that inhibition of the SULT isoforms can alter both endogenous and xenobiotic metabolism. All these articles explore the effects of POPs as direct enzyme inhibitors, actions which would not be found by genomic or proteomic studies since alterations in gene/protein expression are not involved. Recent research has shown that environmental compounds have the capacity to alter the methylation status of DNA sequences and so to affect gene expression.