ABSTRACT
I. Introduction ............................................................................................................... 214 A. Placental Structure and Function •.................................•..........................•••........ 214 B. Xenobiotic Metabolism ....................................................................................... 214 C. Maternal Physiological Influences ..•..•..................................••.........................•. 215
II. Oxidative/Reductive/Hydrolytic Metabolism ........................................................... 215 A. Introduction ...•••......•..•••......•..•.•..••••......•••...........•.....•....••.•••..••..••••.••.•...•.....•••.•.•. 215 B. Oxidations ........................................................................................................... 215 C. Reduction Reactions ...........•••••....•...••.•...........•....•...•...........•...........•.....•..........•. 218 D. Hydrolytic Reactions and Hydrations ................................................................ 219
III. Conjugative Metabolism ..........................•........•.......•.......•.............•...............•...•..... 220 A. Glutathione S-Transferase(s) .......•.................•.......•.....••.•..•.....•..............•........... 220 B. Acylation ............................................................................................................. 221 C. Glucuronidation, Methylation, Sulfation ............................................................ 221
IV. Steroid Metabolism Related to Xenobiotic Transformation .................................... 222 A. Introduction ...................•.............•.............•.•........................••.......•........•.....•....•. 222 B. Androgens to Estrogens (Aromatases) ............................................................... 223 C. Other Conversions .............................................................................................. 223
V. Xenobiotics of Special Interest ..•.......•.•..•.......................•...................................•..... 224 A. Chlorinated and Nonchlorinated Hydrocarbons ................................................. 224 B. Pesticides ............................................................................................................. 224 C. Metals .................................................................................................................. 225 D. Therapeutic Agents and Other Drugs ................................................................. 225
VII. Summary and Conclusions ...•...•.....•.................••..•..........•.•...........•......•....•.........•..... 230
Acknowledgments ............................................................................................................... 230
References ........................................................................................................................... 230
Thus, the placenta is the first fetal organ to be exposed to exogenous substances. 1.2 Although the general structural unit was recognized by Aristotle as early as 350 B.C., the present term "placenta" was not applied until the rnid-1500s. A clear understanding of the structure and functional significance of the human placenta was not achieved until the end of the 1600s, and Hunter's work in the mid-1700s represented the first sophisticated, integrated description. 3 By the 1880s, a detailed understanding of the placental circulation, including the intervillous space, was available. However, only since the 1930s and 1940s has placental physiology received intensive study, and information gained since the mid-1950s represents the majority of our knowledge regarding placental metabolism and transport. The proposal that the human placenta be included as a model system in which to test new drugs emphasizes the recognition that the organ plays a critical role in maternofetal nutrition and, perhaps, metabolism.4-'
Manson and Wise 6 characterized the placenta as "a lipid membrane that permits bidirectional transfer of substances between maternal and fetal compartments" rather than as a barrier. Treatment of fetal disease by drug administration to the mother relies on this characteristic of selective permeability, as well as a predictable rate of metabolism for those substances which undergo transformation.7 The function of the placenta as a partial, selective barrier to some exogenous substances ("xenobiotics") is recognizable in the simpler choriovitelline form present in rodents, as well as in the chorioallantoic form which is present in higher mammals. 8
B. XENOBIOTIC METABOLISM Although the placenta acts as a limited permeability barrier to substances with a molecular
weight (MW) greater than 1000, but does not exclude agents of MW <600 to 800,3•6 metabolic processes which act to degrade or transform large-MW molecules to smaller or altered forms are of significant interest. Young 9 provided an early review of techniques for studies of placental transport and metabolism.
