Comments on the Jayjock et al. paper

Establishing hormesis as an evolution-based biological phenomenon requires a broad discussion of its implications for currently used risk paradigms. The Jayjock et al. papers provide an industrial hygienist's perspective and, as such, represent a valuable contribution to this discussion. Our comments outline a toxicologist's view on the limits and practicability of the Jayjock et al. suggestions. The arguments are primarily based on the shape of dose and time responses and associated variabilities and uncertainties.     

Assessment of Variance in Bioavailability Studies: Comments on the Article by McNamara et al.

Pharmaceutical Research -     

Cancer Biology and Hormesis: Comments on Calabrese (2005)

Large numbers of chemicals of a variety of types exhibit apparent hormetic effects on cultured human cancer cells, causing stimulation of cell growth or related changes at low doses, followed by inhibition at higher doses. Many of the studies listed are not fully convincing, due to lack of appropriate controls or sufficient number of doses. However, the proposed hormetic response seems firmly established in a subset of these experiments. Significance with regard to in vivo cancer growth has not been pursued and must be a priority for the future. For several examples where in vivo titers are known, such as, resveratrol, suramin, and tamoxifen, comparison of the dose and concentration ranges confirms that hormesis could be an issue in vivo. Further investigations are warranted, especially for therapeutic drugs, phytochemicals, and environmental toxicants.     

A vision for the future? A commentary on 'Sociology and Substance Use' by McKeganey et al. (2005)

In 2005 the UK Government's Foresight programme published a paper by Neil McKeganey and colleagues on “Sociology and Substance Use”. The Foresight programme is led by the Government's Office of Science and Innovation with the aim of “producing challenging visions of the future to ensure effective strategies now”. This commentary asks whether the analyses of substance use meet the objectives of the Foresight programme. On a range of issues it contends that the paper either fails to weigh the different strands of evidence or fails to analyse pertinent research. The section on policy focuses entirely on repressive measures as a response to the paper's apocalyptic vision of over 1 million problematic drug users in the UK. Given the paper's title it is surprising that there is no attempt to consider policies which may be more relevant to the psychological and social functions of substance use in modern society.     

Arylamine N-acetyltransferases: a structural perspective. Comments regarding the BJP paper by Zhou et al., 2013

This letter is a comment on Zhou et al. (2013). Arylamine N-acetyltransferases: a structural perspective. Br J Pharmacol 169: 748–760. To view this article visit http://dx.doi.org/10.1111/bph.12182We have read with great interest the recent review published by the British Journal of Pharmacology entitled ‘Arylamine N-acetyltransferases: A structural perspective’ (Zhou et al., 2013). This review highlights, from a structural point of view, the importance of the arylamine N-acetyltransferases (NAT) family of xenobiotic-metabolizing enzymes in the biotransformation of aromatic amine drugs and carcinogens and describes emerging new functions these enzymes may possess. The determination of the three-dimensional structure of prokaryotic and eukaryotic NAT enzymes has led to many advances in the understanding of their catalytic mechanisms, substrate specificity and the effect of polymorphisms on their function. In addition, the elucidation of these crystal structures has also contributed to the development of specific inhibitors of certain NAT isoforms (Sim et al., 2012). Although the review by Zhou et al., (2013) is topical and of great interest, several important elements described below would complete the overview of NAT structure and function.As of 5 April 2013, the Protein Databank (PDB) contains 15 crystal structures of NAT enzymes (from eight prokaryotic NATs and two human NATs). This number of crystal structures has not changed since February 2012. In particular, Zhou et al., (2013) overlooked three crystal structures that were published in the last 5 years: Nocardia farcinica NAT [PDB 3D9W, (Martins et al., 2008)], Mycobacterium marinum NAT in complex with hydralazine drug [PDB 3LTW, (Abuhammad et al., 2010)] and Bacillus anthracis NAT1 in complex with coenzyme A [PDB 3LNB, (Pluvinage et al., 2011)]. In addition, the structure of an NAT isoform from Bacillus cereus has been deposited in the PDB (4DMO) and its coordinates will be available in May 2013; the crystallization of this NAT enzyme was published early last year (Kubiak et al., 2012).The structure of M. marinum NAT complexed with hydralazine sheds light on the binding of this drug to an NAT enzyme and reveals a novel mechanism for the acetylation reaction that results in the production of a 3-methyltriazolo[3,4-a]phthalazine ring compound (Abuhammad et al., 2010). In addition, the structure of NAT1 from B. anthracis in complex with coenzyme A (CoA) demonstrates that the 17-residue insertion previously described as specific to human NAT enzymes (and, more broadly, to mammalian NAT isozymes) is also present in certain prokaryotic NAT enzymes (Pluvinage et al., 2011). This structure also reveals a new mode of binding of the cofactor CoA when compared with the crystal structures of M. marinum NAT and human NAT2 (Pluvinage et al., 2011). Thus, the mode of binding of acetylCoA is more diverse than originally thought and varies among NAT enzymes.Another point pertinent to the review deals with the models for the chemical reaction that occurs at the NAT active site. The authors do describe the important work done by Wagner/Hanna''s group on the hamster NAT2 enzyme showing, in particular, the existence of a thiolate-imidazolium pair at the active site (Wang et al., 2004; 2005). However, the work done by Blanchard and colleagues on a prokaryotic NAT enzyme (the NAT from Mycobacterium tuberculosis), which identified a completely different mechanism from that observed with the hamster NAT2 (Sikora et al., 2008), also deserves attention. In essence, Sikora et al. found that the enzyme has a catalytic cysteine pKa higher than 10, suggesting that the catalytic residue must be protonated at physiological pH and in the presence of substrate before nucleophile attack on acetylCoA occurs. Furthermore, these data do not corroborate the existence of a thiolate/imidazolium ion pair at physiological pH but, rather, indicate a general base catalysis for the M. tuberculosis NAT enzyme. This finding suggests that the catalytic mechanism of NAT enzymes from different organisms can also vary.This letter should not be viewed as a negative commentary on the article of Zhou et al., who have provided a clear and straightforward review of the exciting novel aspects of the NAT field. On the contrary, we hope our letter complements their review and provides further information on these important aspects of NAT structure and function.