Barking up the wrong genome--we are not alone

Pharmacogenetic studies, to help us understand variability in human drug response, have hitherto focussed largely on our own germline mutations, and in the context of anticancer and antimicrobial drugs, also on mutations of the tumour cell or invader microorganism. Here, we wish to draw attention to how our microbiome may contribute to variability in drug effects.

Irinotecan, a prodrug which is activated to the topoisomerase I inhibitory metabolite (SN-38), is commonly used for the treatment of a range of cancers. SN-38 is subsequently detoxified by uridine diphosphate-glycosyltransferase 1, encoded by the UGT1A1 gene. It is well known that the variant allele UGT1A*18 is associated with the more common adverse effects of irinotecan. A recent study shows that the potentially dose-limiting irinotecan-induced diarrhoea is due to enterohepatic circulation of SN-38, and its reactivation in the gut by bacterial β-glucuronidases. Importantly, the authors used specific inhibitors of the microbial enzymes to reduce the gastro-intestinal toxicity in mice.

We draw attention to the increasing range of diseases, including diabetes and obesity, associated with our microbiome. This pharmacogenetic example reminds us that in personalized medicine, there is more than our own genome to take account of.