So far we have only considered damage caused by ‘small’ groups such as methyl groups. There is, however, a class of so-called ‘bulky’ DNA-damaging agents that have been widely studied. Many polyaromatic hydrocarbons (PAH) induce skin cancer in experimental systems and one such molecule benzo(a)pyrene, BaP), is found in tobacco smoke. BaP itself is an extremely stable and unreactive molecule, but it is metabolised within the cell to a highly reactive derivative that forms characteristic DNA modifications at the C2 amino group of guanine. The C2 amino group is normally ‘buried’ within the inner core of the DNA double helix, but the BaP metabolite is small enough to fit into the minor groove of DNA. Here it reacts with the guanine and intercalates between the stacked bases, thereby distorting the helix (Figure 21).