UGT1A1 binding pocket, the carboxyl groups appear to be accessible to
glucuronidation. Monoglucuronides at the 8 or 12 position and a diglucur-
onide are the major products. The enzyme is also capable of forming xylose
and glucose conjugates with the corresponding UDP-sugar.
3.1.2.1 Steroids Estrogens, androgens, progestogens are all substrates for
the enzyme. Estrogens are conjugated at both the 3-OH and 17-OH
positions by either glucuronic acid or sulfate. These conjugates (particularly
sulfates) are the major circulating forms and may serve as a reservoir for the
body. Glucuronides are excreted into urine and bile. Estradiol and ethinyl
estradiol are conjugated by a UGT1A1 at the 3- position (Ebner, 1993). An
important detoxification function of UGTs is to glucuronidate the catechol
estrogens, for example 2-OH and 4-OH estradiol. Catechol estrogens
(potential mutagens and carcinogens) are glucuronidated by UGT1A1,
UGT1A3, UGT2B4, and UGT2B7. UGT1A1 and UGT1A3 have much
better activity for 2-OH estradiol whereas UGT2B4 and UGT2B7 prefer 4-
OH-estradiol (Cheng, 1998). These UGT2B enzymes are present in breast
tissue and in breast tumor lines such as MCF-7 cells (Turgeon, 2001) and may
help prevent mutations leading to breast cancer. Aldosterone (a glucocorticoid)
and its metabolites are glucuronidated by UGT2B7. Glucuronidation of
androgens, for example, androsterone, androstane-3a,17b-diol are catalyzed
by UGT2B15 and UGT2B17, two forms that are present in the prostate and in
liver. UGT2B17 has a greater glucuronidation efficiency for dihydrotestosterone
than UGT2B15.
Other endogenous substrates include lipids, especially pharmacologically
active arachidonic acid metabolites such as 12 and 15-HETE (hydroxyeicosa-
tetraenoic acid), 13-HODE (hydroxyoctadecaenoic acid), and leukotriene B4
that are substrates for UGT2B7, UGT2B10, UGT2B11, as well as other
enzymes. Bile acids such as lithocholic acid and hyodeoxycholic acid are
catalyzed by specific UGT2B forms (UGT2B4 and UGT2B7). UGT1A3 also
has activity for some bile acids (via conjugation at the COOH group). Other
endogenous substrates include vitamin D and its metabolites and vitamin A
analogs (retinoic acid). Finally, thyroid hormones such as thyroxine are also
glucuronidated to inactive forms. Positions of glucuronidation of bile acids and
steroids are shown in Fig. 3.4.
3.1.2.2 Glycolipids Sulfated, glucuronic acid-containing glycolipids (cera-
mides) are present in the peripheral nerves and cauda equina (Chou et al.,
1991).
3.1.3 Enzyme Multiplicity
Like the P450 multigene family, there are several different isozymes present in
two gene families. There are three major gene families:
40 CONJUGATIVE METABOLISM OF DRUGS