In this study, we compared the enzymatic reduction of 10 drugs with a ketone group by homogeneous carbonyl reductase, aldehyde reductase and three dihydrodiol dehydrogenases of human liver cytosol. At least one and in some cases all of the three dihydrodiol dehydrogenases reduced each of the ten drugs. Among these naloxone, naltrexone, befunolol, ethacrynic acid and ketoprofen were substrates specific for the dehydrogenases. The other drugs--haloperidol, metyrapone, loxoprofen, daunorubicin and acetohexamide--were highly reduced by carbonyl reductase and/or aldehyde reductase. The dihydrodiol dehydrogenases also showed lower Km values for haloperidol and loxoprofen than did carbonyl reductase. The results indicate that the three dihydrodiol dehydrogenases, as well as the two reductases, are implicated in the reduction of ketone-containing drugs in human liver cytosol.