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There are a number of reliable studies that have mainly investigated the effects of D4 on the liver and induction of liver enzymes (Dow Corning Corporation, 1996d, 1998, 2002a,b, 2005a, Falany & Li, 2005, McKim et al., 2001b). There are also two reliable studies into the effects of D4 on the release of prolactin (Dow Corning Corporation, 2010a, b).

Additional information

Inhalation of D4 in rats lead to transient dose-dependent cell proliferation and sustained hypertrophy of the liver. Cell proliferation was at its maximum at Day 6 and then subsided until Day 27 of treatment. There was also an increase in thyroid weight and thyroid cell proliferation. These changes are similar to those observed with phenobarbital (Dow Corning Corporation, 2002b, McKim et al., 2001b).

There are five reliable studies that investigate hepatic enzyme activation by D4.

It has been demonstrated in vivo in rats that inhaled D4 acts like a phenobarbital-like inducer of hepatic microsomal enzymes in rats (Dow Corning Corporation, 1996d). This effect on hepatic enzymes has been further characterised in vitro (XenoTech, 1998) using human liver microsomes. D4 appeared to be a non-competitive inhibitor of human CYP2B6, CYP2D6 and CYP3A4/5; a competitive inhibitor of human CYP1A2; either a competitive or non-competitive inhibitor of CYP2C19. D4 had little or no capacity to inhibit rat CYP1A2 and human CYP2A6, CYP2C9 and CYP4A9/11 activity or to function as a metabolism-dependent (reversible or irreversible) inhibitor of any of the P450 enzymes examined, with the possible exception of rat CYP1A1/2 and human CYP3A4/5 which were weakly inhibited by D4 in a reversible metabolism-dependent manner. D4 appeared to be non-competitive inhibitor of rat CYP2B1/2. Another in vitro study noted that the constitutive androstane receptor (CAR) is a nuclear receptor that has been shown to be a key regulator in phenobarbital-induced up-regulation of CYP2B1/2 gene expression. and that the in vivo induction of CYP2B1/2 expression by D4 suggests the possibility that D4 is an activator of CAR in the rat (Dow Corning Corporation, 2005a). Species selectivity for the hepatic responses has been investigated in a study on rats and guinea pigs (Dow Corning Corporation, 2002a). It was shown that rats have an increase in liver weights following treatment with D4 or phenobarbital, but this was not the case for guinea pigs. The authors of the study concluded that in general, the findings of D4 in rat liver were similar to those observed with phenobarbital, but it was not clear if the effects of D4 were in response to D4, D4 metabolites or if the effects represent responses to D4-induced effects on some other organ system. It has also been demonstrated that D4 has different inductive properties in female rats of different ages and reproductive status, and that D4 administered to the pregnant dam is capable of inducing CYP expression in fetal liver and decreasing fetal body weight (Falany & Li, 2005).

There are two reliable studies that investigated the potential effects of D4 on serum prolactin concentrations (Dow Corning Corporation, 2010a, b). These studies showed that inhaled D4 did not decrease prolactin concentrations in Fischer 344 rats.