Xenobiotic resistance in animals, plants, yeast, and bacteria is known to i
nvolve ATP binding cassette transporters that efflux invading toxins. We pr
esent data from yeast and a higher plant indicating that xenobiotic resista
nce also involves extracellular ATP degradation. Transgenic upregulation of
ecto-ATPase alone confers resistance to organisms that have had no previou
s exposure to toxins. Similarly, cells that are deficient in extracellular
ATPase activity are more sensitive to xenobiotics. On the basis of these an
d other supporting data, we hypothesize that the hydrolysis of extracellula
r ATP by phosphatases and ATPases may be necessary for the resistance confe
rred by P-glycoprotein.