Carcinogenesis. 1989 Sep;10(9):1719-24.  

Lack of promoting effect of clonazepam on the development of
N-nitrosodiethylamine-initiated hepatocellular tumors in mice is correlated with
its inability to inhibit cell-to-cell communication in mouse hepatocytes.

Diwan BA, Lubet RA, Nims RW, Klaunig JE, Weghorst CM, Henneman JR, Ward JM, Rice
JM.

Biological Carcinogenesis and Development Program Resources, Inc., National
Cancer Institute, Frederick, MD 21701-1013.

The tumor-promoting ability of clonazepam (CZP), a widely used benzodiazepine
anticonvulsant, was investigated in an in vivo mouse liver tumor promotion assay
and an in vitro mouse hepatocyte intercellular communication assay. The
development of preneoplastic hepatocellular foci of cellular alteration and
hepatocellular neoplasms was studied in male B6C3F1 mice initiated, at 5 weeks
of age, with a single i.p. injection of N-nitrosodiethylamine (NDEA; 90 mg/kg
body weight) in tricaprylin, followed by administration of either phenobarbital
(PB; 0.05%) or CZP (0.068% or 0.136%) in diet beginning 2 weeks after carcinogen
injection and continuing to 60 weeks of age. Several mice from each group were
killed after 9, 21, 33 or 53 weeks on test diet, and portions of liver and other
organs were fixed in formalin and examined histologically. Unlike PB, CZP did
not promote the development of preneoplastic hepatocellular foci or neoplasms
(adenomas and carcinomas) in NDEA-initiated mice. Following limited (2 weeks)
dietary exposure at 0.15%, CZP was a potent inducer of hepatic P450IIB1-mediated
alkoxyresorufin O-dealkylase activities. In contrast, the degree of induction in
hepatic tissue from mice fed 0.136% CZP for 53 weeks was markedly lower than
that in mice fed 0.05% PB for 53 weeks. In the in vitro assay, diazepam, a
strong tumor promoter in mouse liver, significantly inhibited mouse hepatocyte
gap junctional intercellular communication, while CZP had no significant effect
on this parameter. Thus, CZP, a drug structurally related to diazepam, is
inactive as a liver tumor promoter in mice.

PMID: 2766464 [PubMed - indexed for MEDLINE]