Dietary isothiocyanates as confounding factors in the molecular epidemiology of colon cancer.

In this issue, Lin et a!. ( 1) show convincing statistics that subjects exposed to dietary broccoli who have a GSTM 12 null phenotype are less susceptible to colon cancer than those who are GSTMI positive. The expected effect of a GSTM1 null phenotype is greater, not less, susceptibility to cancers due to reduced carcinogen detoxification by GSTM1 (2, 3). Broccoli reverses this outcome for two reasons: (a) it contains sulforaphane, a cancer chemopreventive isothiocyanate (4) that present evidence indicates both inhibits cytochrome P450 (and therefore carcinogen activation) and induces GSTs, consequently increasing carcinogen detoxification (57); and (b) sulforaphane is itself a substrate for GSTs, which may abolish its anticarcinogenic activity (8, 9). Because Lin et a!. suggest that their findings are the consequence of reduced conjugation of sulforaphane among GSTM 1 null subjects ( I), this commentary will attempt to assemble data available relating to this hypothesis to assess its validity. Their study has an interesting practical outcome because dietary isothiocyanates have rarely, if ever, been taken into account in investigations of the molecular epidemiology of cancer, and it is probable that they have been confounding factors in a number of studies (3) and should be borne in mind in the design of future protocols. Lin et a!. (1) have observed a significant effect of a broccoli diet on susceptibility to colon cancer, even without taking into consideration exposure to specific colon carcinogens. To analyze the processes upon which their findings might be based, it is necessary to select a known colon carcinogen with a reasonably well-understood pharmacology, such as the food-borne heterocyclic amine PhIP, which has been associated with human colon carcinogenesis (10). GSTA1, GSTA2, and GSTM 1 (in those individuals that have the gene) are most abundant in the liver and small intestine but low in occurrence in colon ( 1 1 ). PhIP in food enters the circulation via the small intestine and passes immediately to the liver. The liver, taking into account its large mass and rich