Biomedical Engineering Reference
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shorter duration, thereby reducing the potential for suffering. To date, zebrafish
proteomic and transcriptomic studies investigating pharmaceuticals have revealed
certain similarities to mammalian models and verified the presence of existing
mammalian biomarkers such as glutathione S-transferase and aldehyde dehydroge-
nase (unpublished data), but more validation is still required.
8.7 CONCLUSIONS
Hepatotoxicity is one of the main causes of drug attrition in the pharmaceutical
industry but of the assays currently being performed, no single assay or battery of
screens is able to reliably predict all hepatotoxic compounds. Therefore, although in
vitro assays have significantly improved, many candidate drugs only get identified as
toxic in the most strongly regulated mammalian models, or once in use by humans.
Zebrafish hepatotoxicity models have shown great promise and have become more
widely accepted in recent years. Good correlation with mammals, the ability to
identify toxic metabolites, and drug-drug interactions associated with CYP3A4,
make this model a valuable addition to other traditional screens, but more validation is
still required as various classes of drugs are yet to be evaluated and ways to further our
understanding of the underlying mechanisms of liver toxicity in zebrafish are
warranted.
REFERENCES
A
BBOUD
G and K
APLOWITZ
N (2007). Drug-induced liver injury. Drug Saf 30(4): 277-294.
A
LLENDE
ML, A
MSTERDAM
A, B
ECKER
T, K
AWAKAMI
K, G
AIANO
N, and H
OPKINS
N (1996). Insertional
mutagenesis in zebrafish identifies two novel genes, pescadillo and dead eye, essential for embryonic
development. Genes Dev 10(24): 3141-3155.
A
MALI
AA, R
EKHA
RD, L
IN
CJ, W
ANG
WL, G
ONG
HY, H
ER
GM, and W
U
JL (2006). Thioacetamide induced
liver damage in zebrafish embryo as a disease model for steatohepatitis. J Biomed Sci 13(2): 225-232.
A
MATRUDA
JF, S
HEPARD
JL, S
TERN
HM, and Z
ON
LI (2002). Zebrafish as a cancer model system. Cancer Cell
1(3): 229-231.
B
ARROS
TP, A
LDERTON
WK, R
EYNOLDS
HM, R
OACH
AG, and B
ERGHMANS
S (2008). Zebrafish: an emerging
technology for in vivo pharmacological assessment to identify potential safety liabilities in early drug
discovery. Br J Pharmacol 154(7): 1400-1413.
B
ARUT
BA and Z
ON
LI (2000). Realizing the potential of zebrafish as a model for human disease. Physiol
Genomics 2(2): 49-51.
B
RAUNBECK
T, G
ORGE
G, S
TORCH
V, and N
AGEL
R (1990). Hepatic steatosis in zebra fish (Brachydanio rerio)
induced by long-term exposure to gamma-hexachlorocyclohexane. Ecotoxicol Environ Saf 19(3):
355-374.
B
RESOLIN
T,
DE
F
REITAS
R
EBELO
M, and C
ELSO
D
IAS
B
AINY
A (2005). Expression of PXR, CYP3A and MDR1
genes in liver of zebrafish. Comp Biochem Physiol C Toxicol Pharmacol 140(3-4): 403-407.
C
ARNEY
SA, P
ETERSON
RE, and H
EIDEMAN
W (2004). 2,3,7,8-Tetrachlorodibenzo-p-dioxin activation of the
aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator pathway causes developmental
toxicity through a CYP1A-independent mechanism in zebrafish. Mol Pharmacol 66(3): 512-521.
CDC (2007). Behavioral Risk Factor Surveillance System Survey Data. U.S. Department of Health and
Human Services, Centers for Disease Control and Prevention, Atlanta, GA.
C
HEN
JN, H
AFFTER
P, O
DENTHAL
J, V
OGELSANG
E, B
RAND
M,
VAN
E
EDEN
FJ, F
URUTANI
-S
EIKI
M, G
RANATO
M,
H
AMMERSCHMIDT
M, H
EISENBERG
CP, J
IANG
YJ, K
ANE
DA, K
ELSH
RN, M
ULLINS
MC, and N
USSLEIN
-
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