# PERINATAL MECHANISMS OF DETOXIFICATION

> **NIH NIH R37** · SCRIPPS RESEARCH INSTITUTE, THE · 1994 · $325,113

## Abstract

Our overall objectives are to characterize how the functional diversity
and regulation of the multiple forms of cytochrome P450 affect the
capacity of the organism and particularly the fetus, newborn nd mother to
respond to the insult of foreign chemicals (xenobiotics). A determination
of how physiologic processes influence the metabolism of xenobiotics and
conversely, how xenobiotics can alter the metabolism of hormones and
other endogenous substances may provide a key to understanding how the
capacity to metabolize xenobiotics is regulated during pregnancy and the
perinatal period. This understanding can facilitate the selection of
drugs for which adequate detoxicative pathways are available and the
identification of factors that determine the susceptibility of the
immature to the detrimental effects of foreign chemicals. The focus of
this proposal is the Cyp4A family of cytochrome P450 monooxygenases which
includes a prostagiandin w-hydroxylase that is greatly elevated in the
rabbit lung during pregnancy. The Cyp4A gene that is differentially
expressed during pregnancy in the rabbit lung is being cloned and
characterized. Gene tmnsfer experiments will be employed to identify
cis-acting control elements of this gene. In addition, footprinting
assays will be used to determine whether the progesterone receptor binds
to this control element of the gene. The Cyp4A family is diverse as
indicated by the identification and characterization of several Cyp4A
cDNAs in our laboratory. The corresponding enzymes have been expressed in
eukaryotic cells by transient transfection of the cDNAs in appropriate
expression vectors. The capacities of these enzymes to catalyze the
w-hydroxylation of fatty acids including arachidonic acid, prostaglandins
as well as drugs such as sodium valproate will be 11 investigated. Human
cDNAs will also be cloned in order to define the diversity of Cyp4A genes
in humans by sequence analysis and expression of the enzyme from the
cloned CDNA. Some Cyp4A P450s are induced by hypolipemic drugs such as
clofibrate or the plasticizer diethylhexylphthalate. Cell lines will be
identified that respond to clofibrate with the induction of Cyp4A enzymes
as judged by hybridization of mRNAs with CDNA probes and immunoblot
analysis of microsomal proteins. Cyp4A genes encoding the inducible
enzymes will be cloned using the cDNAs as probes. Regulatory regions of
the clofibrate-responsive gene will be identified by gene transfer
experiments as described earlier for the Cyp4A gene induced by
progesterone. DNA-protein binding assays will be used to identify the
protein factors that interact with the clofibrate-responsive cis-acting
control elements identified in the previous experiments. The
identification and characterization of the cellular components that
mediate the induction of P450 genes in response to foreign chemicals is a
central question regarding our capacity to regulate the metabolism of
toxic chemicals.

## Key facts

- **NIH application ID:** 2194853
- **Project number:** 4R37HD004445-25
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **SAM.gov UEI:** PHZJFZ32NKH4
- **Principal Investigator:** ERIC F JOHNSON
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1994
- **Award amount:** $325,113
- **Award type:** 4N
- **Project period:** 1978-09-29 → 1999-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/2194853

## Citation

> US National Institutes of Health, RePORTER application 2194853, PERINATAL MECHANISMS OF DETOXIFICATION (4R37HD004445-25). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/2194853. Licensed CC0.

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