Among gastrointestinal distributed isozymes encoded at the UGT1 locus, UDP-glucuronosyltransferase 1A10 (UGT1A10) metabolizes a number of important chemicals. Similar to broad conversion of phytoestrogens (Basu, N. K., Ciotti, M., Hwang, M. S., Kole, L., Mitra, P. S., Cho, J. W., and Owens, I. S. (2004) J. Biol. Chem. 279, 1429 -1441), UGT1A10 metabolized estrogens and their derivatives, whereas UGT1A1, -1A3, -1A7, and -1A8 differentially exhibited reduced activity toward the same. UGT1A10 compared with UGT1A7, -1A8, and -1A3 generally exhibited high activity toward acidic nonsteroidal anti-inflammatory drugs and natural benzaldehyde derivatives, while UGT1A3 metabolized most efficiently aromatic transcinnamic acids known to be generated from flavonoid glycosides by microflora in the lower gastrointestinal tract. Finally UGT1A10, -1A7, -1A8, and -1A3 converted plant-based salicylic acids; methylsalicylic acid was transformed at high levels, and acetylsalicylic (aspirin) and salicylic acid were transformed at moderate to low levels. Atypically UGT1A10 transformed estrogens between pH 6 and 8 but acidic structures preferentially at pH 6.4. Furthermore evidence indicates UGT1A10 expressed in COS-1 cells depends upon phosphorylation; UGT1A10 versus its single, double, and triple mutants at three predicted protein kinase C phosphorylation sites incorporated [ 33 P]-orthophosphate and showed a progressive decrease with no detectable label or activity for the triple T73A/T202A/ S432G-1A10 mutant. Single and double mutants revealed either null/full activity or null/additive activity, respectively. Additionally UGT1A10-expressing cultures glucuronidated 17-[ 14 C]estradiol, whereas cultures containing null mutants at protein kinase C sites showed no estrogen conversion. Importantly UGT1A10 in cells supported 10-fold higher glucuronidation of 17-estradiol than UGT1A1. In summary, our results suggest gastrointestinally distributed UGT1A10 is important for detoxifying estrogens/phytoestrogens and aromatic acids with complementary activity by UGT1A7, -1A8, -1A3, and/or -1A1 evidently dependent upon phosphorylation.Many aromatic chemicals are taken into the body unwittingly as components of plant-based diets and as therapeutic agents. Although there are several different categories of chemicals in dietary plants, the flavonoids are by far the largest group and include quasiactive phytoestrogens, which often mimic endogenous estrogens due to structural similarities (1). Additionally there are non-flavonoid-type estrogenic chemicals in plants, e.g. coumestrol and zearalenone, which are reported to have toxic effects in the body (2). While it is known that phytoestrogens can have beneficial tumor-suppressing activity (3) and other effects (4), it is not generally known that the chemicals can also be destructive to animal reproductive systems as shown by the collapse and emaciation of the reproductive and urinary systems of livestock that grazed on clovers and crops with high phytoestrogen content (2). Additionally the phytoest...