1. The activities of the ethoxycoumarin O-deethylase (ECOD), epoxide hydrolase (EH), UDP-glucuronyl transferase (GT), glutathione S-transferase (GST), acetyl transferase (AT) and sulphotransferase (ST) were measured in 6 liver, 8 lung, 8 kidney, 8 intestinal mucosa and 22 urinary bladder mucosa specimens from human subjects. EH and GT were studied with styrene oxide and 1-naphthol, respectively, as substrates, GST, AT and ST were studied with benzo(a)pyrene-4,5-oxide, p-aminobenzoic acid and 2-naphthol, respectively. 2. The enzyme activities were detectable at significant rates in liver, lungs, kidneys and gut. In urinary bladder, EH, GT, GST and ST only were detectable. The liver catalyzed the various reactions at higher rates than did other tissues. 3. Of the extrahepatic tissues, the intestinal mucosa contained the highest activities of AT (50% of liver) and ST (30% of liver), whereas kidneys contained the highest activity of GT (50% of liver) and GST (80% of liver). GST was the enzyme with the widest tissue distribution.

Acetyltransferase with p-aminobenzoic acid (PABA) as substrate was investigated in the cytosolic fraction of the placenta, liver, adrenals, lungs, kidneys, intestine from human fetuses and the liver, lungs, kidneys and intestinal mucosa from adult subjects. All tissue specimens assayed catalyzed the acetylation of PABA at a significant rate. The activity (expressed as nmol of product formed/min/mg protein; mean ± SE) was 1.10 ± 0.59 in the fetal liver, 0.66 ± 0.04 in the placental and 3.87 ± 0.53 in the adult liver cytosol. Among the fetal tissues, the adrenals had the highest (2.36 ± 0.78) and the gut the lowest activity (0.71 ± 0.11). The acetyltransferase activity (mean ± SE) in the lungs, kidneys and intestinal mucosa from adult subjects was 1.19 ± 0.15; 1.34 ± 0.04 and 3.80 ± 0.34, respectively.

Sulfotransferase with 2-naphthol as substrate was investigated in the cytosolic fraction of human fetal liver, lungs, kidneys, adrenal glands, intestine and placenta and also in liver, lungs, kidneys, intestinal and urinary bladder mucosa from human adult subjects. All tissue specimens assayed catalyzed the sulfation of 2-naphthol at a significant rate. The activity (expressed as pmole per minute per milligram protein; mean ± SD) was 211 ± 197 (n = 46) fetal liver; 22 ± 12 (n = 29) placenta; 625 ± 205 (n = 42) human adult liver. In fetal kidneys (576 ± 177; n = 6) and gut (558 ± 293; n = 6) the activity was twice as high as in liver. In the lungs (273 ± 125; n = 6) and in the adrenals (174 ± 119; n = 19) the sulfotransferase activity was comparable with the hepatic one. In human adult extrahepatic tissues the highest activity was found in the intestinal mucosa (153 ± 49; n = 4) and the lowest one in the urinary bladder mucosa (16 ± 4; n = 4). This paper shows that the sulfotransferase has a wide distribution in the human fetus and the distribution pattern of this enzyme is different in the human fetus and adult subject.

The activity of the microsomal glucuronyltransferase (GT) was measured in 34 fetal and 27 adult human livers with 2-naphthol as substrate. The average ( ± SD) enzyme activity was 0.07 ± 0.07 nmol/min/mg protein (fetal) and 7.98 ± 4.19 nmol/min/mg protein (adult) livers. The adult to fetal ratio of the GT activity was 114. The activity of the cytosolic sulphotransferase (ST) was measured with 2-naphthol as substrate in 30 fetal and 23 adult livers. ST activity (mean ± SD) was 0.18 ± 0.12 nmol/min/mg protein (fetal) and 0.63 ± 0.22 nmol/min/mg protein (adult). The adult to fetal ratio of the ST activity was 3.5. The postnatal development of GT is more marked than that of ST. In the fetal livers, the rate of 2-naphthol sulfation correlated (p < 0.01) with the rate of 2-naphthol glucuronidation, whereas they did not correlate in the adult livers. No relationship was observed between the activity of the GT or ST and gestational age. The correlation existing between ST and GT in human fetus might suggest that the two enzymes are under a common developmental pattern which seems to be independent of gestational age. The activity of the GT with morphine as substrate was measured in 25 fetal and 29 adult livers and found to be 0.23 ± 0.20 nmol/ min/mg protein (fetal) and 1.85 ± 0.98 nmol/min/mg protein (adult). Thus, the adult to fetal ratio of morphine glucuronidation was 8. The isoenzyme of the GT catalyzing the conjugation of planar molecules such as 2-naphthol seems to be less developed than that catalyzing the conjugation of bulkier molecules such as morphine in fetus at midgestation.

Glutathione S-transferase (GST) was investigated with benzo(a)pyrene-4,5-oxide (BPO) as substrate in tissue specimens from 26 fetal and 27 adult livers and 27 placentas. The average (+/- SEM) of GST activity in the cytosol was 1.80 +/- 0.18 (fetal liver), 3.05 +/- 0.30 (adult liver) and 1.18 +/- 0.07 (placenta) nmol/min/mg. GST was also investigated in human fetal and adult lungs, kidneys and gut. In these tissues the average (+/- SEM) GST activity ranged between 0.71 +/- 0.12 (adult intestine) and 2.11 +/- 0.18 (fetal lungs) nmol/min/mg. Whereas in the fetal liver the conjugation of BPO was catalyzed at a rate of about two-thirds of the adult rate, similar or higher GST activities were found in the fetal non-hepatic tissues as compared to the adult organs. No correlation was found between the activity of the GST in fetal liver and placenta and the gestational age (11-25 weeks). GST develops before the 11th week of gestation and it does not undergo changes during the mid-gestation. No correlation was found between GST activity in adult liver and age (32-70 years).

The activity of sulphotransferase towards 2-naphthol and the concentration of its endogenous substrate, adenosine 3'-phosphate 5'-phosphosulphate (PAPS), have been measured in five specimens of human liver, lung, and kidney, and the mucosa from the ileum and the ascending, descending and sigmoid colon. The activity of 2-naphthol sulphotransferase (mean nmol.min-1.mg-1 protein) was 1.82 (liver); 0.034 (kidney); 0.19 (lung); 0.64 (ileum); 0.47 (ascending colon); 0.50 (descending colon); 0.40 (sigmoid colon). The concentration of PAPS (mean nmol.g-1 wet tissue) was 22.6 (liver); 4.8 (kidney); 4.3 (lung); 12.8 (ileum); 8.1 (ascending colon); 7.5 (descending colon); 6.2 (sigmoid colon). The concentration of PAPS and the activity of 2-naphthol sulphotransferase were higher in the liver than in the extrahepatic tissues. There was significant difference between ileum and ascending colon, both the activity of sulphotransferase and the concentration of PAPS being higher in the former. 2-Naphthol sulphotransferase activity and the concentration of PAPS have consistent distribution patterns. Differences between the tissues studied were more marked for sulphotransferase than for its endogenous substrate.

1 The activities of microsomal glucuronyltransferase and thiomethyltransferase, and those of cytosolic sulphotransferase, acetyltransferase, glutathione transferase and thiomethyltransferase were measured in abnormal (cirrhosis and chronic hepatitis) and normal livers. 2 Glucuronyltransferase and sulphotransferase were investigated with 2-naphthol and ethinyloestradiol as substrates. p-Aminobenzoic acid, benzo(a)pyrene-4,5-epoxide and 2-mercaptoethanol were the substrates of acetyltransferase, glutathione transferase and thiomethyltransferase, respectively.3 Enzyme activities are expressed as nmol min-1 incubation mg-1 protein and the averages (± s.d.) are given. With 2-naphthol as substrate, the glucuronyltransferase activity was 6.55 ± 4.10 (abnormal liver, n = 33) and 7.81 ± 4.02 (normal liver, n = 26) (NS); whereas sulphotransferase activity was 0.28 ± 0.18 (abnormal liver, n = 35) and 0.68 ± 0.43 (normal liver, n = 26) (P < 0.01). Glucuronyltransferase activity towards ethinyloestradiol was 102.5 ± 56.9 (abnormal liver, n = 30) and 107 ± 59.9 (normal liver, n = 26) (NS), whereas sulphotransferase activity was 57.2 ± 36.0 (abnormal liver, n = 35) and 122 ± 67.6 (normal liver, n = 28) (P < 0.01). Acetyltransferase activity was 0.84 ± 0.83 (abnormal liver, n = 35) and 3.84 ± 1.65 (normal liver, n = 26) (P < 0.01). Glutathione transferase activity was 0.83 ± 0.68 (abnormal liver, n = 35) and 2.90 ± 1.59 (normal liver, n = 25) (P < 0.01) and thiomethyltransferase activity was 1.00 ± 0.69 (abnormal liver, n = 34) and 3.99 ± 1.49 (normal liver, n = 25) (P < 0.01). 4 Liver disease lowers the activities towards the substrates studied of sulphotransferase, acetyltransferase, glutathionetransferase and thiomethyltransferase but not that of glucuronyltransferase. Thus, overall hepatic conjugating capacity is decreased in liver injury. However, enzyme activity is substrate dependent and it is not possible to extrapolate the results for other compounds.

1 The effect of antipileptic drug valpromide (VPM) on the activity of epoxide hydrolase was studied in human adult and foetal liver, kidneys, lungs, intestine and in placenta. The activity of the epoxide hydrolase was measured with both styrene oxide and benzo(a)pyrene-4,5-oxide as substrates. 2 VPM inhibited the epoxide hydrolase obtained from all organs studied. The degree of inhibition was independent of the substrate used.3 A lowering of the epoxide hydrolase activity by 50% was observed when the concentration of VPM was similar to that of the substrates. 4 VPM competitively inhibited the activity of adult liver epoxide hydrolase with styrene oxide as substrate.