Characterization of Phase I and Phase II hepatic drug metabolism activities in a panel of human liver preparations

• Published in: Chemico-biological interactions Vol. 118; no. 2; pp. 151 - 169
• Main Authors: Iyer, Krishna R, Sinz, Michael W
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 01.04.1999
• Subjects: Arylamine N-Acetyltransferase - analysis; Catalysis; Catechol O-Methyltransferase - analysis; Cytochrome P-450 Enzyme System - analysis; Cytochrome P450; Cytosol; Female; Glucuronosyltransferase - analysis; Glutathione - analysis; Human; Humans; Liver - enzymology; Liver bank; Male; Microsomes; Microsomes, Liver - enzymology; NADP - analysis; Oxygenases - analysis; Pharmaceutical Preparations - metabolism; Phase I enzymes; Phase II enzymes; Tissue Banks; Human; BSA, bovine serum albumin; ADME, absorption, distribution, metabolism, and elimination; GST, glutathione S-transferase; NDE, new drug entity; Cytochrome P450; Phase II enzymes; UDPGT, UPD-glycosyl transferases; Cytosol; Liver bank; Microsomes; TBAP, tetrabutylammonium phosphate; DTT, dithiothreitol; TPMT, thiopurinemethyl transferase; FMO, flavin monooxygenase; COMT, catechol O-methyl transferase; ST, sulfotransferases; NAT, N-acetyl transferases; NADPH, nicotine adenine dinucleotide phosphate; Phase I enzymes; CYP, cytochrome P450
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/S0009-2797(99)00007-1

The role of drug metabolism in drug discovery (lead compound selection) and the traditional role of identifying the enzymes involved in biotransformation pathways (reaction phenotyping) have both relied heavily on the availability and use of a human liver bank. The assessment of drug metabolizing enzyme activity and variability in a series of individual human livers is essential when characterizing the enzymes involved in metabolic pathways (i.e. correlation analysis). In this regard, a human liver bank of 21 samples (14 males, six females, and one unknown) was characterized with respect to the activity of several important drug metabolizing enzymes. The total CYP450 content of the livers ranged from 0.06 to 0.46 nmol/mg microsomal protein. The fold variations found in specific enzyme contents were as follows: CYP1A2 (3×), CYP2A6 (21×), CYP2C9 (8×), CYP2C19 (175×), CYP2D6 (18×), CYP2E1 (5×), CYP3A4 (18×), FMO (2.5×), UDPGT (4×), NAT (7×), COMT (5×), ST (5×), TPMT (3×), and GST (2.5×). In general, the fold variation of the Phase II enzymes was lower compared with the Phase I enzymes, with the exceptions of CYP1A2, CYP2E1, and FMO. Similar data were reviewed from other established liver banks and compared with regard to the relative variability observed in drug metabolizing capacities found in this study.