Characterization of Human Fetal Hepatic Cytochrome P-450-Associated 7-Ethoxyresorufin O-Deethylase and Aryl Hydrocarbon Hydroxylase Activities by Monoclonal Antibodies

Abstract

Two cytochrome P-450-dependent enzyme activities, 7-ethoxyresorufin O-deethylase (ERDE) and aryl hydrocarbon hydroxylase (AHH) were measured in liver microsomes from 7 human fetuses. Monoclonal antibodies (MAb) to a 3-methylcholanthrene- induced (MAb 1-7-1) and a phenobarbital-induced (MAb 2-66-3) rat hepatic cytochrome P-450 were used to measure the contribution of the MAb-defined, epitope-specific cytochromes P-450 to the total reaction measured for the above activities. MAb 1-7-1 inhibited fetal hepatic ERDE activity to a variable extent (from 0 to 100%, 34 in average), but had only negligible effects on AHH activity (mean inhibition 9 %). The contribution of induction by cigarette smoking to the variability of ERDE inhibition by MAb 1-7-1 remained unclear. MAb 2-66-3 inhibited ERDE activity by 18% and AHH activity by 12%. In comparisons with earlier studies on adult liver and placental microsomes, the present results with fetal liver suggest that there are differences in cytochrome P-450- associated ERDE and AHH activities between these tissues, which might be due to different tissue-specific isoenzyme patterns.

7‐Ethoxycoumarin and 7‐Ethoxyresorufin O‐Deethylase in Human Foetal and Adult Liver: Studies with Monoclonal Antibodies

“…Pelkonen et al 1986;Pasanen et al (1987) arrived at similar results with human adult liver although the MAb 1-7-1 inhibiting potency varied more (0 to 65 per cent) than in our material. These data suggest that there are at least two enzymes or classes of enzymes responsible for 7-ethoxyresorufin 0deethylation since only 21 to 36 per cent of the activity was blocked by MAb 1-7-1.…”

“…The other P-450 is responsible for only a part of 7-ethoxyresorufin 0-deethylation. Pelkonen et al 1986;Pasanen et al (1987) arrived at similar results with human adult liver although the MAb 1-7-1 inhibiting potency varied more (0 to 65 per cent) than in our material. This may be due to a difference in the environmental exposure of the individuals from whom the tissue was collected.…”

“…Our values are in the same range as those in human adult liver specimens from smoking and non-smoking individuals (Pelkonen et al 1986;Pasanen et al 1987). In most specimens, the rate of 0-deethylation of 7-ethoxyresorufin was about twice that of 7-ethoxycoumarin.…”

“…In most specimens, the rate of 0-deethylation of 7-ethoxyresorufin was about twice that of 7-ethoxycoumarin. Our values are in the same range as those in human adult liver specimens from smoking and non-smoking individuals (Pelkonen et al 1986;Pasanen et al 1987).…”

The Ontogeny of Human Drug-Metabolizing Enzymes: Phase I Oxidative Enzymes: Table 1

“…Evidence for the presence of constitutively expressed CYP1A1 enzyme in the fetus is compelling. In 1987, Pasanen et al (1987) reported ethoxyresorufin O-deethylase (EROD) activity in seven fetal liver samples (unreported gestational age) that was inhibited to a variable extent by an anti-rat CYP1A1 monoclonal antibody. Similarly, Yang et al (1995) demonstrated EROD activity (6.2 pmol/min/mg of microsomal protein) in 8 to 10 pooled embryonic liver samples at 7 to 9 weeks estimated gestational age.…”