We studied the effects of semisynthetic (elemental) diets on the function and morphology of the human small intestine. The enzymatic capacity of the intestinal mucosa to metabolize lipophilic xenobiotics was investigated using jejunal biopsy specimens from 15 normal subjects who were on an isocaloric, nutritionally balanced semisynthetic diet for 7 days and thereafter on a normal home diet. Each subject underwent biopsy twice: on day 7 of semisynthetic diet and again on home diet 2-6 wk later. The jejunal mucosal tissue was examined by histologic morphometry and stereomicroscopy. Moreover, 25-50 mg of the biopsy material was homogenized and the following enzyme activities were determined in 20,000 g supernatant: for cytochrome P450-dependent monooxygenase activity with 7-ethoxycoumarin O-deethylase (EOD) and with nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome c reductase and for conjugation activity with 1-naphthol glucuronyltransferase (NGT). The NGT and reductase activities were unchanged by the dietary alterations. However, the EOD activity was significantly depressed on semisynthetic diet and rose to control range on home diet (from 5.3 +/- 2.5 to 12.4 +/- 8.6 pmol/min X 10 mg wet wt). Male subjects had significantly higher EOD activities than female subjects on semisynthetic diet (6.6 +/- 2.3 vs. 3.2 +/- 0.9) as well as on home diet (16.3 +/- 9.0 vs. 6.4 +/- 3.0). Semisynthetic diet also reduced the jejunal villous height significantly when compared with home diet (408 +/- 49 vs. 373 +/- 44 micron). Therefore, on semisynthetic diet the toxicity of dietary xenobiotics that are inactivated by the intestinal mucosa may be increased.